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ͳ „•–”ƒ –ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ ʹ —•ƒ‡ˆƒ••—‰ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ ͵ ‹•–‘ˆ ‹‰—”‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͺ  Ͷ ‹•–‘ˆƒ„Ž‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͺ ͷ ›„‘Ž•ƒ†„„”‡˜‹ƒ–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ ͸ –”‘†— –‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲ ͸Ǥͳ Ž‘‘†’”‡••—”‡ƒ†‹–•”‡‰—Žƒ–‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲ ͸ǤͳǤͳ ›•–‡‹ ”‡‰—Žƒ–‹‘‹–Š‡‘”‘–‡•‹˜‡„‘†›ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲ ͸ǤͳǤͳǤͳ ‡‹Ǧƒ‰‹‘–‡•‹ǦƒŽ†‘•–‡”‘‡•›•–‡ȋȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳ Ͳ  ͸ǤͳǤʹ ‘Ž‡ —Žƒ”‡ Šƒ‹••‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘‘ ‡ŽŽ—Žƒ”Ž‡˜‡ŽǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳʹ ͸ǤͳǤʹǤͳ ‘†—Žƒ–‘”•‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳʹ ͸ǤͳǤʹǤͳǤͳ ‰‹‘–‡•‹ ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳ͵ ͸ǤͳǤʹǤͳǤʹ †”‡‘ ‘”–‹ ‘–”‘’‹ Š‘”‘‡ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͶ ͸ǤͳǤʹǤͳǤ͵ ‘–ƒ••‹—ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͷ ͸ǤͳǤʹǤͳǤͶ –”‹ƒŽƒ–”‹—”‡–‹ ’‡’–‹†‡ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͷ ͸ǤͳǤʹǤʹ œ›‡•‹˜‘Ž˜‡†‹ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†–Š‡‹””‡‰—Žƒ–‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͷ ͸ǤͳǤʹǤʹǤͳ Ž†‘•–‡”‘‡•›–Šƒ•‡ȋCYP11B2ȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͷ ͸Ǥʹ Žƒ••‡•‘ˆ‹‘ Šƒ‡Ž•‘ˆƒŒ‘”‹–‡”‡•–ˆ‘”–Š‹•™‘”ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳ͸ ͸ǤʹǤͳ ‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͺ ͸ǤʹǤͳǤͳ Ǧ–›’‡ƒ†Ǧ–›’‡ Šƒ‡Ž•ƒ†–Š‡‹””‘Ž‡‹ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͲ ͸ǤʹǤʹ ’”‘–‡‹Ǧ ‘—’Ž‡†‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹʹ ͸ǤʹǤʹǤͳ ’”‘–‡‹Ǧ ‘—’Ž‡†‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž‹•‘ˆ‘”•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͵ ͸ǤʹǤʹǤͳǤͳ ‹”͵ǤͶȀ ͶȀ ͷǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͷ ͸Ǥ͵ ›’‡”–‡•‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͸ ͸Ǥ͵Ǥͳ –‹Š›’‡”–‡•‹˜‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹ͹ ͸Ǥ͵Ǥʹ ”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͺ ͸Ǥ͵ǤʹǤͳ Ž†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͳ ͸Ǥ͵ǤʹǤͳǤͳ KCNJ5—–ƒ–‹‘•‹ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒ•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͳ ͸Ǥ͵ǤʹǤͳǤʹ CACNA1D—–ƒ–‹‘•‹ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒ•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͵ ͸Ǥ͵ǤʹǤͳǤ͵ ƒ•‡—–ƒ–‹‘•‹ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵ͷ ͸Ǥ͵ǤʹǤͳǤͶ CTNNB1—–ƒ–‹‘•‹ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒ•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͹ ͸Ǥ͵ǤʹǤͳǤͷ ‘”‹‰‹•ƒ†–Š‡”‘Ž‡‘ˆƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ‡ŽŽ Ž—•–‡”•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵ͺ ͸Ǥ͵ǤʹǤʹ ƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͲ ͸Ǥ͵ǤʹǤʹǤͳ Ž— ‘ ‘”–‹ ‘‹†Ǧ”‡‡†‹ƒ„Ž‡Š›’‡”ƒŽ†‘•–‡”‘‹•Ȃ ”‘••‹‰Ǧ‘˜‡”„‡–™‡‡ CYP11B1ƒ†CYP11B2ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͲ ͸Ǥ͵ǤʹǤʹǤʹ ƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ Ȃˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•™‹–Š —‘™ ƒ—•‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͲ ͸Ǥ͵ǤʹǤʹǤ͵ ƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ȂKCNJ5‰‡”Ž‹‡—–ƒ–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶʹ ͸Ǥ͵ǤʹǤʹǤͶ ”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•™‹–Š•‡‹œ—”‡•ƒ†‡—”‘Ž‘‰‹ ƒ„‘”ƒŽ‹–‹‡•Ȃ ‰‡”Ž‹‡CACNA1D—–ƒ–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶ͵ ͸Ǥ͵ǤʹǤʹǤͷ ƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ǦCACNA1H‰‡”Ž‹‡—–ƒ–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͶ ͸Ǥ͵ǤʹǤʹǤ͸ —–ƒ–‹˜‡”‘Ž‡•‘ˆARMC5‹ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶ͸ ͸Ǥ͵ǤʹǤ͵ ‡ŽŽŽ‹‡•ƒ•‘†‡Ž•ˆ‘”’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶ͹ dĂďůĞŽĨĐŽŶƚĞŶƚƐ

͹ ”‘Œ‡ –•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͲ ͹Ǥͳ ‘˜‡Ž•‘ƒ–‹ —–ƒ–‹‘•‹’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ”‡”‡Žƒ–‡†–‘–Š‡ Ž‹‹ ƒŽǡ ”ƒ†‹‘Ž‘‰‹ ƒŽƒ†’ƒ–Š‘Ž‘‰‹ ƒŽ’Š‡‘–›’‡ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͲ ͹ǤͳǤͳ „Œ‡ –‹˜‡•‘ˆ–Š‡™‘”ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͲ ͹ǤͳǤʹ ƒ—• ”‹’–ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͲ ͹Ǥʹ ƒ ”‘Ž‹†‡••‡Ž‡ –‹˜‡Ž›‹Š‹„‹–—–ƒ– ͷ’‘–ƒ••‹— Šƒ‡Ž•–Šƒ– ƒ—•‡ƒŽ†‘•–‡”‘‡Ǧ ’”‘†— ‹‰ƒ†‡‘ƒǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͳ ͹ǤʹǤͳ „Œ‡ –‹˜‡•‘ˆ–Š‡’”‘Œ‡ –ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͳ ͹ǤʹǤʹ ƒ—• ”‹’–ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͳ ͹Ǥ͵ ͳ ͳͷͶͻ—–ƒ– ƒŽ ‹— Šƒ‡Ž ƒ—•‡•ƒ—–‘‘‘—•ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ͳͷ ‡ŽŽ•ƒ†‹•‹Š‹„‹–‡†„›‹„‡ˆ”ƒ†‹ŽǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷʹ ͹Ǥ͵Ǥͳ „Œ‡ –‹˜‡•‘ˆ–Š‡’”‘Œ‡ –ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷʹ ͹Ǥ͵Ǥʹ ƒ—• ”‹’–ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷʹ ͹ǤͶ ˜‡•–‹‰ƒ–‹‘•‘ˆ–Š‡CACNA1HS1073C˜ƒ”‹ƒ–ǣˆˆ‡ –•‘CYP11B2‡š’”‡••‹‘ƒ† ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽŽ‹‡ ͳͷ‹ ‘’ƒ”‹•‘–‘CACNA1HM1549VǤ ͷ ͵  ͹ǤͶǤͳ „Œ‡ –‹˜‡•‘ˆ–Š‡’”‘Œ‡ –ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͵ ͹ǤͶǤʹ ƒ–‡”‹ƒŽ•ƒ†‡–Š‘†•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͵ ͹ǤͶǤʹǤͳ ƒ–‹‡–•ƒ†—–ƒ–‹‘†‹• ‘˜‡”›ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͵ ͹ǤͶǤʹǤʹ Š‡‹ ƒŽ•ǡ„—ˆˆ‡”•ƒ†’”‹‡”•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͵ ͹ǤͶǤʹǤ͵ ‡ŽŽ —Ž–—”‡ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͶ ͹ǤͶǤʹǤͶ Žƒ•‹†•ƒ† Ž‘‹‰ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͶ ͹ǤͶǤʹǤͷ ”ƒ•ˆ‡ –‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͷ ͹ǤͶǤʹǤ͸ Ž†‘•–‡”‘‡ ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͷ ͹ǤͶǤʹǤ͸Ǥͳ •‘Žƒ–‹‘‘ˆ–‘–ƒŽ•‘Ž—„Ž‡’”‘–‡‹ˆ”‘ ‡ŽŽ•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͷ ͹ǤͶǤʹǤ͹ “ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͸ ͹ǤͶǤʹǤͺ –ƒ–‹•–‹ ƒŽƒƒŽ›•‹•ƒ†•‘ˆ–™ƒ”‡ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͸ ͹ǤͶǤ͵ ‡•—Ž–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷ͸ ͹ǤͶǤͶ ‘ Ž—•‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͻ ͺ ‹• —••‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ ͳ  ͺǤͳ —–ƒ–‹‘•ƒ†–Š‡‹” ‘””‡Žƒ–‹‘™‹–Š’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ͳ ͺǤͳǤͳ —–ƒ–‹‘ˆ”‡“—‡ ‹‡•ƒ”‡Žƒ”‰‡Ž›‹ƒ ‘”†ƒ ‡™‹–Š’”‡˜‹‘—•”‡’‘”–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ͳ ͺǤͳǤʹ —–ƒ–‹‘•”‡Žƒ–‡–‘’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ ʹ  ͺǤͳǤ͵ ‘ Ž—•‹‘ƒ†‘—–Ž‘‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸͵ ͺǤʹ ƒ ”‘Ž‹†‡•ƒ”‡„Ž‘ ‡”•‘ˆ ͷ—–ƒ– Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸Ͷ ͺǤʹǤͳ  ͷ Šƒ‡Ž„Ž‘ ‡”•”‡†— ‡ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†‰‹˜‡‡™‹’—Ž•‡•ˆ‘”–Š‡ †‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘ˆ ’ƒ–‹‡–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ͷ ͺǤʹǤʹ ‘’ƒ”‹•‘™‹–Š’”‡˜‹‘—••–—†‹‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸͸ ͺǤʹǤ͵ —–Ž‘‘ǣ —–—”‡•–—†‹‡•‘ˆ Šƒ‡Ž‹Š‹„‹–‘”•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸͹ ͺǤ͵ Invitro‹˜‡•–‹‰ƒ–‹‘•‘ˆ–Š‡‡ˆˆ‡ –•‘ˆCACNA1H—–ƒ–‹‘•‘CYP11B2‡š’”‡••‹‘ƒ† ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ͺ ͺǤ͵Ǥͳ ͳ ͳͷͶͻ‹ ”‡ƒ•‡•ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†CYP11B2‡š’”‡••‹‘‹ ͳͷ ‡ŽŽ• ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͸ͺ ͺǤ͵ǤͳǤͳ ‘’ƒ”‹•‘‘ˆ‘—”ˆ‹†‹‰•‘CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘™‹–Š ‘–Š‡”•–—†‹‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͸ͻ ͺǤ͵ǤͳǤʹ ͳ ͳͷͶͻ ƒ„‡‹Š‹„‹–‡†„›Ǧ–›’‡ Šƒ‡Ž„Ž‘ ‡”‹„‡ˆ”ƒ†‹ŽǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹Ͳ ͺǤ͵ǤͳǤ͵ —–Ž‘‘ǣ ˜‡•–‹‰ƒ–‹‰–Š‡‡ˆˆ‡ –•‘ˆͳ ͳͷͶͻ‘ ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹ͳ

 dĂďůĞŽĨĐŽŶƚĞŶƚƐ

ͺǤ͵Ǥʹ CACNA1H S1073C †‘‡• ‘–ƒˆˆ‡ – ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ƒ†CYP11B2 ‡š’”‡••‹‘ ‹ ͳͷ ‡ŽŽ•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹ʹ ͺǤ͵ǤʹǤͳ ‡“—‡ ‡ ‘•‡”˜ƒ–‹‘ƒ†•–”— –—”ƒŽ ‘•‹†‡”ƒ–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹͵ ͺǤ͵ǤʹǤʹ ‹‹–ƒ–‹‘•‘ˆ‘—”•–—†›ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹͵ ͺǤ͵ǤʹǤ͵ —–Ž‘‘ǣ ˜‡•–‹‰ƒ–‹‘•‘ˆ—–ƒ–‹‘•‹ARMC5ƒ†DACH1ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹ͷ ͻ ‡ˆ‡”‡ ‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹͹ ͳͲ ƒ•ƒ‰—‰ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͷ ͳͳ ’’‡†‹šǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͸ ͳͳǤͳ ”‘Œ‡ –•ˆ‡ƒ–—”‡†‹–Š‹•™‘”ƒ† ‘–”‹„—–‹‘•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͸ ͳͳǤͳǤͳ ”‘Œ‡ –ͳȋ‡ –‹‘͹ǤͳȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͸ ͳͳǤͳǤʹ ”‘Œ‡ –ʹȋ‡ –‹‘͹ǤʹȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͸ ͳͳǤͳǤ͵ ”‘Œ‡ –͵ȋ‡ –‹‘͹Ǥ͵ȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͸ ͳͳǤͳǤͶ ”‘Œ‡ –Ͷȋ‡ –‹‘͹ǤͶȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻ͹ ͳͳǤʹ Žƒ•‹†ƒ’•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͺ ͳͳǤ͵ ‡“—‡ ‹‰”‹‡”•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͻ ͳͳǤͶ ‘ˆ–™ƒ”‡—•‡†ˆ‘”–Š‡‰‡‡”ƒ–‹‘‘ˆ–Š‹•–Š‡•‹•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲͲ ͳͳǤͷ —ƒ”›‘ˆ•–—†‹‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲͲ ͳʹ ‹†‡••–ƒ––Ž‹ Š‡”Ž¡”—‰ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͳͳ

 ϭďƐƚƌĂĐƚ

1 Abstract ”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•‹•‘‡•—„ˆ‘”‘ˆ•‡ ‘†ƒ”›Š›’‡”–‡•‹‘–Šƒ– ƒ„‡ ƒ—•‡†ƒ‘‰•–‘–Š‡”•„›„‹Žƒ–‡”ƒŽƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ‘”ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†Ǧ ‡‘ƒ•ȋ•ȌǤ‡ —””‡–•‘ƒ–‹ —–ƒ–‹‘•‹–Š‡‰‡‡•KCNJ5ǡCACNA1DǡATP1A1, ATP1A2 ƒ†CTNNB1Šƒ˜‡„‡‡‹†‡–‹ˆ‹‡†‹•ǤŠ‹Ž‡•‘‡—–ƒ–‹‘•ƒ”‡™‡ŽŽ Šƒ”ƒ –‡”‹œ‡†ǡ”‡Žƒ–‹˜‡Ž›•ƒŽŽƒ‘—–•‘ˆ†ƒ–ƒƒ”‡ƒ˜ƒ‹Žƒ„Ž‡‘‘–Š‡”•ǤŠ‹•™‘” ‘Ǧ –ƒ‹•ƒ•–—†›‹™Š‹ Š–Š‡—–ƒ–‹‘ƒŽ•–ƒ–—•‘ˆ•‹•ƒ– Š‡†–‘–Š‡ ‘””‡•’‘†‹‰ ’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •Ǥ –‹†‡–‹ˆ‹‡•KCNJ5ƒ•–Š‡‘•–ˆ”‡“—‡–Ž›—–ƒ–‡† ‰‡‡‹‘—” ‘Š‘”–ȋ͵͹ǤͳΨȌǤKCNJ5—–ƒ––—‘”•™‡”‡Žƒ”‰‡”ǡƒ’’‡ƒ”‡†Ž‡••†‡•‡‹ ƒ• ƒƒ†Šƒ†ƒœ‘ƒˆƒ• ‹ —Žƒ–ƒǦŽ‹‡ƒ’’‡ƒ”ƒ ‡Ǥƒ–‹‡–•™‹–ŠKCNJ5Ǧ—–ƒ–‡† •™‡”‡‘”‡‘ˆ–‡ˆ‡ƒŽ‡ǡ™Š‹Ž‡ƒŽ‡’”‡†‘‹ƒ ‡™ƒ•‘„•‡”˜‡†ˆ‘”–Š‡‘–Š‡” —–ƒ–‹‘•Ǥ

ƒ›•–—†‹‡• ‘ —”™‹–Š‘—”ˆ‹†‹‰–Šƒ–KCNJ5 ‹•–Š‡‘•–ˆ”‡“—‡–Ž›—–ƒ–‡†‰‡‡ ‹•ǤŠ‡”‡„›ǡ–Š‡ ͳͷͳƒ†ͳ͸ͺƒŽ–‡”ƒ–‹‘•ƒ ‘—–ˆ‘”‘•– ƒ•‡•ǡ™Š‹Ž‡‘–Š‡” —–ƒ–‹‘•ƒ”‡˜‡”›”ƒ”‡ǤŠ‡•‡ ‘†•–—†›‹ Ž—†‡†‹–Š‹•™‘”‹†‡–‹ˆ‹‡•ƒ ”‘Ž‹†‡• ƒ•„Ž‘ ‡”•‘ˆ ͷ ͳͷͳƒ†ͳ͸ͺ Šƒ‡Ž•ǡƒŽ„‡‹––Š‡ ͷ™‹Ž†–›’‡”‡ƒ‹• —ƒˆˆ‡ –‡†„›–Š‡•‡ ‘’‘—†•Ǥ‘š‹–Š”‘› ‹ǡ–Š‡‘•–’”‘‹•‹‰•—„•–ƒ ‡‘—–‘ˆ –Š‹• Žƒ••ǡ‹•ƒ„Ž‡–‘”‡†— ‡„‘–ŠƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†ƒŽ†‘•–‡”‘‡•›–Šƒ•‡‡šǦ ’”‡••‹‘‹ƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽ•‡š’”‡••‹‰ ͷ—–ƒ– Šƒ‡Ž•ǤŽ†‘•–‡”‘‡•›Ǧ –Šƒ•‡‡š’”‡••‹‘™ƒ••‹‹Žƒ”Ž›”‡†— ‡†„›–Š‡‘Ǧƒ–‹„‹‘–‹ ƒ ”‘Ž‹†‡͵ͺǤ  –Š‡ˆ—–—”‡ǡ„Ž‘ ‡”•‘ˆ—–ƒ– ͷ Šƒ‡Ž‹‰Š–’”‡•‡–ƒ‘’–‹‘‹–Š‡†‹ƒ‰‘•‹• ƒ†–”‡ƒ–‡–‘ˆ’ƒ–‹‡–•™‹–ŠKCNJ5—–ƒ–•Ǥ

ƒ‹Ž‹ƒŽˆ‘”•‘ˆŠ›’‡”ƒŽ†‘•–‡”‘‹•Šƒ˜‡„‡‡–”ƒ ‡†„ƒ –‘ƒŽ–‡”ƒ–‹‘•‹–Š‡ƒŽǦ †‘•–‡”‘‡•›–Šƒ•‡‰‡‡CYP11B2ƒ•™‡ŽŽƒ•–‘—–ƒ–‹‘•‹–Š‡‰‡‡•KCNJ5ǡCACNA1D ƒ†CACNA1HǤ ‘™‡˜‡”ǡ•‘‡–‹‡•–Š‡—†‡”Ž›‹‰‰‡‡–‹  ƒ—•‡•”‡ƒ‹—‘™Ǥ Š‡–Š‹”†•–—†›‹ Ž—†‡†‹–Š‹•™‘”•—„•–ƒ–‹ƒ–‡•–Š‡”‘Ž‡‘ˆ–Š‡‰‡”Ž‹‡CACNA1H M1549V—–ƒ–‹‘ƒ•ƒ ƒ—•‡‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ǤŠ‡˜ƒ”‹ƒ–™ƒ• ˆ‹”•–†‹• ‘˜‡”‡†‹’ƒ–‹‡–•™‹–Š‡ƒ”Ž›Ǧ‘•‡–’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ†‡Ž‡ –”‘Ǧ ’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡••—‰‰‡•–‡†ƒ‰ƒ‹‘ˆˆ— –‹‘‘ˆ–Š‡—–ƒ– Šƒ‡Ž•Ǥ—”‹˜‡•–‹Ǧ ‰ƒ–‹‘••Š‘™–Šƒ–ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†ƒŽ†‘•–‡”‘‡•›–Šƒ•‡‡š’”‡••‹‘‹•‹Ǧ ”‡ƒ•‡†‹ƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–Š—–ƒ–CACNA1H‹ ‘’ƒ”‹•‘–‘–Š‡ ™‹Ž†–›’‡ǤŠ‹•‡ˆˆ‡ – ƒ„‡”‡†— ‡†‘”‡˜‡ƒ„”‘‰ƒ–‡†„›–Š‡Ǧ–›’‡ ƒŽ ‹— Šƒ‡Ž „Ž‘ ‡”‹„‡ˆ”ƒ†‹ŽǤ‘–Š‡”—–ƒ–‹‘•–—†‹‡†‹–Š‹•™‘”‹•CACNA1H S1073Cǡ™Š‹ Š

ͷ ϮƵƐĂŵŵĞŶĨĂƐƐƵŶŐ ™ƒ•‹†‡–‹ˆ‹‡†‹‘‘œ›‰‘–‹ –™‹•‹•–‡”•™‹–ŠŠ›’‡”ƒŽ†‘•–‡”‘‹•ƒ†–Š‡‹”ˆƒ‹Ž› ‡„‡”•Ǥ”ƒ•ˆ‡ –‹‘‘ˆƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽ•™‹–ŠCACNA1H S1073C†‘‡•‘–”‡•—Ž– ‹†‹ˆˆ‡”‡ ‡•‹ƒŽ†‘•–‡”‘‡•›–Šƒ•‡‡š’”‡••‹‘‘”ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ‘Ǧ ’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ǡ™Š‹ Š•—‰‰‡•–•–Šƒ––Š‡—–ƒ–‹‘‹•‘–†‹•‡ƒ•‡Ǧ ƒ—•‹‰Ǥ

Š‡•–—†‹‡•‹ Ž—†‡†‹–Š‹•™‘”‡Šƒ ‡‘—”—†‡”•–ƒ†‹‰‘ˆ–Š‡—†‡”Ž›‹‰‡ ŠǦ ƒ‹•• ‘ˆ ’”‹ƒ”› Š›’‡”ƒŽ†‘•–‡”‘‹•ǡ „› ‘ˆ‹”‹‰ –Š‡ ”‘Ž‡ ‘ˆ–Š‡CACNA1H M1549V—–ƒ–‹‘‹ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•ƒ†„›Ž‹‹‰—–ƒ–‹‘•–‘ƒ •’‡ ‹ˆ‹ ’Š‡‘–›’‡ǤŠ‡›’”‘˜‹†‡‡™‹’—Ž•‡•ˆ‘”†‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘ˆ’”‹ƒ”› Š›’‡”ƒŽ†‘•–‡”‘‹•ǡ‡•’‡ ‹ƒŽŽ›–Š”‘—‰Š–Š‡‹†‡–‹ˆ‹ ƒ–‹‘‘ˆƒ ”‘Ž‹†‡•ƒ•„Ž‘ ‡”•‘ˆ —–ƒ– ͷ Šƒ‡Ž•Ǥ‡˜‡”–Š‡Ž‡••ǡ‹•‘‡‘ ƒ•‹‘•ǡ–Š‡—†‡”Ž›‹‰‰‡‡–‹ •‘ˆ ’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•”‡ƒ‹— Ž‡ƒ”ǡƒ•‹–Š‡ ƒ•‡‘ˆ–Š‡’ƒ–‹‡–•™‹–Š–Š‡ CACNA1H S1073C—–ƒ–‹‘Ǥ

2 Zusammenfassung ”‹¡”‡” ›’‡”ƒŽ†‘•–‡”‘‹•—• ‹•– ‡‹‡ ‘” †‡” •‡—†¡”‡ ›’‡”–‘‹‡ǡ †‹‡ „‡‹Ǧ •’‹‡Ž•™‡‹•‡†—” Š„‹Žƒ–‡”ƒŽ‡‡„‡‹‡”‡Š›’‡”’Žƒ•‹‡‘†‡”Ž†‘•–‡”‘Ǧ’”‘†—œ‹‡”‡†‡ †‡‘‡ȋȌ˜‡”—”•ƒ Š–™‹”†Ǥ‹‡†‡”‡Š”‡†‡•‘ƒ–‹• Š‡—–ƒ–‹‘‡‹†‡ ‡Ǧ ‡KCNJ5ǡCACNA1DǡATP1A1ǡATP2B3—†CTNNB1™—”†‡‹‹†‡–‹ˆ‹œ‹‡”–Ǥ ò” ‡‹‹‰‡†‹‡•‡”—–ƒ–‹‘‡‹•–‡‹–›’‹• Š‡”Ž‹‹• Š‡”Š¡‘–›’Žƒ”‡–ƒ„Ž‹‡”–ǡ™‘Š‹‰‡Ǧ ‰‡ˆò”ƒ†‡”‡†‹‡ƒ–‡Žƒ‰‡†ò‹•–Ǥ‹‡•‡”„‡‹–„‡‹ŠƒŽ–‡–‡‹‡–—†‹‡ǡ†‹‡‡‹‡‡”Ǧ „‹†—‰œ™‹• Š‡†‡ ‡‘–›’—††‡‡–•’”‡ Š‡†‡—‘”Ǧ—†ƒ–‹‡–‡Ǧ ‡”ƒŽ‡Š‡”•–‡ŽŽ–Ǥ‹‡–—†‹‡‹†‡–‹ˆ‹œ‹‡”–KCNJ5ƒŽ•†ƒ•ƒŠ¡—ˆ‹‰•–‡—–‹‡”–‡ ‡ ‹—•‡”‡”‘Š‘”–‡ȋ͵͹ǤͳΨȌǤ‹‡„‡–”‡ˆˆ‡†‡—‘”‡™ƒ”‡‰”Ú釔ǡŠƒ––‡‡‹™‡Ǧ ‹‰‡”†‹ Š–‡•”• Š‡‹—‰•„‹Ž†‹ ƒ—†¡Š‡Ž–‡‹‹Š”‡” ‹•–‘Ž‘‰‹‡Š¡—ˆ‹‰†‡” ‘ƒˆƒ• ‹ —Žƒ–ƒǤǦƒ–‹‡–‡‹–KCNJ5—–ƒ–‹‘™ƒ”‡Š¡—ˆ‹‰‡”™‡‹„Ž‹ Šǡ™‘Š‹Ǧ ‰‡‰‡†‹‡ƒ–‹‡–‡‹–ƒ†‡”‡—–ƒ–‹‘‡ò„‡”™‹‡‰‡†¡Ž‹ Š™ƒ”‡Ǥ

ƒŠŽ”‡‹ Š‡–—†‹‡•–‹‡†ƒ”‹ò„‡”‡‹ǡ†ƒ••KCNJ5†ƒ•ƒŠ¡—ˆ‹‰•–‡—–‹‡”–‡ ‡ ‹‹•–Ǥƒ„‡‹†‡ ‡†‹‡G151R—††‹‡L168R —–ƒ–‹‘†‹‡‡‹•–‡ ¡ŽŽ‡ƒ„ǡ™¡ŠǦ ”‡†ƒ†‡”‡—–ƒ–‹‘‡•‡Ž–‡•‹†Ǥ‹‡•‡”„‡‹–„‡‹ŠƒŽ–‡–‡‹‡œ™‡‹–‡–—†‹‡ǡ†‹‡ ƒ”‘Ž‹†‡ƒŽ•Ž‘ ‡”—–‹‡”–‡” ͷƒ¡Ž‡‹†‡–‹ˆ‹œ‹‡”–ǡ™‘„‡‹‹Ž†–›’ƒ¡Ž‡‹ Š– „‡‡‹–”¡ Š–‹‰– ™‡”†‡Ǥ ‘š‹–Š”‘› ‹ǡ †‹‡ ˜‹‡Ž˜‡”•’”‡ Š‡†•–‡ —„•–ƒœ ƒ—• †‹‡•‡” –‘ˆˆŽƒ••‡ǡ•‡–•‘™‘ŠŽ†‹‡Ž†‘•–‡”‘’”‘†—–‹‘ƒŽ•ƒ— Š†‹‡Ž†‘•–‡”‘Ǧ›–Šƒ•‡ š’”‡••‹‘‹‡„‡‹‡”‡ƒ”œ‹‘œ‡ŽŽ‡‹–—–‹‡”–‡ ͷǤ‹‡Ž†‘•–‡”‘Ǧ›Ǧ –Šƒ•‡š’”‡••‹‘™—”†‡†—” Š†ƒ•‹ Š–Ǧƒ–‹„‹‘–‹• Š‡ƒ”‘Ž‹†͵ͺ‹¡ŠŽ‹ Š‡”

͸ ϮƵƐĂŵŵĞŶĨĂƐƐƵŶŐ ‡‹•‡‰‡Š‡–Ǥ †‡”——ˆ–Ú–‡Ž‘ ‡”—–‹‡”–‡” ͷƒ¡Ž‡‹†‡”‹ƒ‰Ǧ ‘•‡—†‡Šƒ†Ž—‰˜‘ƒ–‹‡–‡‹–KCNJ5—–ƒ–‹‘‡‡‹‰‡•‡–œ–™‡”†‡Ǥ

ƒ‹Ž‹¡”‡ ‘”‡†‡•’”‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—•‘–‡œ—‡‹Žƒ—ˆ‡”¡Ǧ †‡”—‰‡ ‹ Ž†‘•–‡”‘Ǧ›–Šƒ•‡ ‡ CYP11B2ǡ •‘™‹‡ ‹ KCNJ5ǡ CACNA1D—† CACNA1Hœ—”ò ‰‡ˆòŠ”–™‡”†‡Ǥ‹ Š–•†‡•–‘–”‘–œ•‹††‹‡œ—‰”—†‡Ž‹‡‰‡†‡‰‡‡–‹Ǧ • Š‡ ƒ–‘”‡‹ƒ Š‡ ¡ŽŽ‡—„‡ƒ–Ǥ‹‡†”‹––‡–—†‹‡‹†‹‡•‡””„‡‹–—–‡”Ǧ ƒ—‡”–†‹‡‘ŽŽ‡˜‘CACNA1H M1549VƒŽ•”•ƒ Š‡˜‘ˆƒ‹Ž‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘Ǧ ‹•—•›’ Ǥ‹‡—–ƒ–‹‘™—”†‡‹ƒ–‹‡–‡‡–†‡ –ǡ†‹‡„‡”‡‹–•‹‹Š”‡”‹†Š‡‹– ƒ’”‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—•‡””ƒ–™ƒ”‡ǤŽ‡–”‘’Š›•‹‘Ž‘‰‹• Š‡–—†‹‡ †‡—–‡–‡ƒ—ˆ‡‹‡ ƒ‹‘ˆ — –‹‘†‡”—–‹‡”–‡ƒ¡Ž‡Š‹Ǥ•‡”‡–‡”•— Š—‰‡ œ‡‹‰‡ǡ†ƒ••Ž†‘•–‡”‘Ǧ›–Šƒ•‡š’”‡••‹‘—†Ž†‘•–‡”‘’”‘†—–‹‘‹‡„‡‹‡Ǧ ”‡ƒ”œ‹‘œ‡ŽŽ‡‹–ͳ ͳͷͶͻ‹‡”‰Ž‡‹ Šœ—‹Ž†–›’‡”ŠÚŠ–•‹†Ǥ‹‡Ǧ •‡”ˆˆ‡–ƒ†—” Š†‡Ǧ›’ƒŽ ‹—ƒƒŽ„Ž‘ ‡”‹„‡ˆ”ƒ†‹Žƒ„‰‡• Š™¡ Š–‘†‡” ‰ƒ”‡Ž‹‹‹‡”–™‡”†‡Ǥ‹‡™‡‹–‡”‡—–ƒ–‹‘ǡ†‹‡‹†‹‡•‡””„‡‹–—–‡”•— Š–™‹”†ǡ‹•– CACNA1H S1073CǤ‹‡•‡ƒ”‹ƒ–‡™—”†‡‹‡‹‡‹‹‰‡™‹ŽŽ‹‰‡‹–’”‹¡”‡ ›’‡”Ǧ ƒŽ†‘•–‡”‘‹•—•—††‡”‡ ƒ‹Ž‹‡‹–‰Ž‹‡†‡”‡–†‡ –Ǥ‹‡”ƒ•ˆ‡–‹‘˜‘‡Ǧ „‡‹‡”‡ƒ”œ‹‘œ‡ŽŽ‡‹–CACNA1H S1073C ”‡•—Ž–‹‡”–™‡†‡”‹‡‹‡”‡”ŠÚŠ–‡ŽǦ †‘•–‡”‘’”‘†—–‹‘‘ Š‹‡‹‡”‡”ŠÚŠ–‡Ž†‘•–‡”‘Ǧ›–Šƒ•‡š’”‡••‹‘‹‡”Ǧ ‰Ž‡‹ Šœ—‹Ž†–›’ǤƒŠ‡”‹•–ƒœ—‡Š‡ǡ†ƒ••†‹‡CACNA1H S1073C—–ƒ–‹‘‹ Š– ”ƒŠ‡‹–•˜‡”—”•ƒ Š‡†‹•–Ǥ

‹‡‹†‹‡•‡””„‡‹–‡–ŠƒŽ–‡‡–—†‹‡˜‡”„‡••‡”—•‡”‡”•–¡†‹•†‡”†‡’”‹Ǧ ¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—•œ—‰”—†‡Ž‹‡‰‡†‡‡ Šƒ‹•‡ǡ‹†‡•‹‡†‹‡‘ŽŽ‡ †‡”CACNA1H M1549V—–ƒ–‹‘‹ˆƒ‹Ž‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—•„‡•–¡–‹‰‡—† ‡‹‡‡”ò’ˆ—‰œ™‹• Š‡—–ƒ–‹‘‡‹—†‡‹‡•’‡œ‹ˆ‹• Š‡Š¡‘–›’Š‡”Ǧ •–‡ŽŽ‡Ǥ‹‡˜‡”‹––‡Ž‡—‡ ’—Ž•‡ˆò”†‹‡‹ƒ‰‘•‡—†‡Šƒ†Ž—‰˜‘’”‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—•ǡ ‹•„‡•‘†‡”‡ †—” Š †‹‡ †‡–‹ˆ‹œ‹‡”—‰ ˜‘ ƒ”‘Ž‹†‡ ƒŽ• Ž‘ ‡”—–‹‡”–‡” ͷƒ¡Ž‡Ǥ‹ Š–•†‡•–‘–”‘–œ„Ž‡‹„‡†‹‡œ—‰”—†‡Ž‹‡‰‡†‡‰‡Ǧ ‡–‹• Š‡ ƒ–‘”‡ ‹’”‹¡”‡ ›’‡”ƒŽ†‘•–‡”‘‹•—• œ—™‡‹Ž‡—‰‡Ž¡”–ǡ™‹‡ ‹ ƒŽŽ†‡”ƒ–‹‡–‡‹–‡‹‡”CACNA1H S1073C—–ƒ–‹‘Ǥ

͹ ϯ>ŝƐƚŽĨ&ŝŐƵƌĞƐ 3 ListofFigures ‹‰—”‡ͳǤŠ‡”‡‹Ǧƒ‰‹‘–‡•‹ǦƒŽ†‘•–‡”‘‡•›•–‡ȋȌǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳ͵ ‹‰—”‡ʹǤ–‡’•‘ˆƒŽ†‘•–‡”‘‡•›–Š‡•‹•‹–Š‡  ‡ŽŽǡ‡œ›‡•‹˜‘Ž˜‡†ƒ† •—„ ‡ŽŽ—Žƒ”Ž‘ ƒŽ‹œƒ–‹‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳ͹ ‹‰—”‡͵Ǥ‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͻ ‹‰—”‡ͶǤ ™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤʹͶ ‹‰—”‡ͷǤ—‰‰‡•–‡†’ƒ–Š‘‡ Šƒ‹••‘ˆ‹‘ Šƒ‡Žƒ†’—’—–ƒ–‹‘•‹’Ž‹ ƒ–‡† ‹ ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵͸ ‹‰—”‡͸Ǥ ”‡“—‡–Ž›—–ƒ–‡†”‡•‹†—‡•‹‹‘ Šƒ‡Ž•‹’Ž‹ ƒ–‡†‹ ƒ†–Š‡‹” ’‘•‹–‹‘™‹–Š‹‡ƒ Š’”‘–‡‹ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͳ ‹‰—”‡͹Ǥͳ ͳͲ͹͵ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͺ ‹‰—”‡ͺǤCYP11B2‡š’”‡••‹‘Ȍƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Ȍ‹ ͳͷ ‡ŽŽ• –”ƒ•ˆ‡ –‡†™‹–Š‡’–›˜‡ –‘”ǡCACNA1HwtǡS1073C‘”M1549VǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͷͻ ‹‰—”‡ͻǤ ‘‘Ž‘‰—‡•‘ˆ–Š‡’”‘–‡‹”‡‰‹‘• ‘–ƒ‹‹‰Š—ƒͳ ͳͲ͹͵ǡ ͷ͸ͷ͸ƒ† ͳͳͷͶ̴ͳͷͷǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹ Ͷ  ‹‰—”‡ͳͲǤŽƒ•‹†ƒ’‘ˆ’ ʹǦKCNJ5Ǧ‡ ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͺ ‹‰—”‡ͳͳǤŽƒ•‹†ƒ’’͸ǦǦCACNA1HǦ Ǧ Ǧ—”‘ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͻ 

4 ListofTables ƒ„Ž‡ͳǤ—–ƒ–‹‘ˆ”‡“—‡ ‹‡•‹•ƒ ‘”†‹‰–‘†‹ˆˆ‡”‡–•–—†‹‡•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵Ͷ ƒ„Ž‡ʹǤ ‡‡—–ƒ–‹‘•‹•ƒ†–Š‡‹” Šƒ”ƒ –‡”‹•–‹ •ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͵ͻ ƒ„Ž‡͵ǤŠƒ”ƒ –‡”‹•–‹ •‘ˆ ’ƒ–‹‡–•™‹–Š‰‡”Ž‹‡—–ƒ–‹‘•‹‰‡‡•‡ ‘†‹‰‹‘ Šƒ‡Ž•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͶͻ ƒ„Ž‡ͶǤ‘™˜ƒ”‹ƒ–•‹DACH1ƒŽ–‡”‹‰–Š‡—„‡”‘ˆ ‘•‡ —–‹˜‡•‡”‹‡”‡•‹†—‡• •—””‘—†‹‰ͳͷͶ̴ͳͷͷǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤ͹͸ ƒ„Ž‡ͷǤ”‹‡”•—•‡†ˆ‘”’Žƒ•‹†•‡“—‡ ‹‰ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͻͻ ƒ„Ž‡͸Ǥ–—†‹‡•‘ˆKCNJ5—–ƒ–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲͳ ƒ„Ž‡͹Ǥ–—†‹‡•‘ˆCACNA1D—–ƒ–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲͶ ƒ„Ž‡ͺǤ–—†‹‡•‘ˆƒ•‡—–ƒ–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͲ͸ ƒ„Ž‡ͻǤ–—†‹‡•‘ˆCTNNB1—–ƒ–•ǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤǤͳͳͲ 



ͺ ϱ^LJŵďŽůƐĂŶĚďďƌĞǀŝĂƚŝŽŶƐ 5 Symbols and Abbreviations

 ƒ‰‹‘–‡•‹Ǧ ‘˜‡”–‹‰‡œ›‡ ͵ ‹‘•‹–‘Ž–”‹•’Š‘•‘’Šƒ–‡”‡ ‡’–‘”   ƒ†”‡‘ ‘”–‹ ‘–”‘’‹ Š‘”‘‡   gene name encoding members of †ǦͶǡͷ ƒ†”‡ƒŽͶǡͷ the Kir family   ƒ–‹Ǧ†‹—”‡–‹ Š‘”‘‡ ‹” ‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— ‰ Ȁ  ƒ‰‹‘–‡•‹ Ȁ  Šƒ‡Ž  ƒ–”‹ƒŽƒ–”‹—”‡–‹ ’‡’–‹†‡  Ǧ  Ž—–‡‹‹œ‹‰Š‘”‘‡Ȃ Š‘”‹‘‹   ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒ ‰‘ƒ†‘–”‘’‹”‡ ‡’–‘”  ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ‡ŽŽ Ž—•Ǧ ʹ ‡Žƒ‘ ‘”–‹ʹ”‡ ‡’–‘” –‡”• Ȁ ‘–ƒ˜ƒ‹Žƒ„Ž‡ ͷ ƒ”ƒ†‹ŽŽ‘”‡’‡ƒ–Ǧ ‘–ƒ‹‹‰ͷ Ȁ ‘–†‡–‡”‹‡†  ƒŽ†‘•–‡”‘‡Ǧ–‘Ǧ”‡‹”ƒ–‹‘  ‘”–Š‡”‹ ƒ ͳȀʹ ƒ‰‹‘–‡•‹”‡ ‡’–‘”ͳ  ‡”˜‡‰”‘™–Šˆƒ –‘” ”‡•’‘•‡ ͳͳ •‘†‹—Ȁ’‘–ƒ••‹—Ǧ–”ƒ•’‘”–‹‰ ‡Ž‡‡– ƒ•‡•—„—‹–ƒŽ’ŠƒǦͳ  •‘†‹— ŠŽ‘”‹†‡•›’‘”–‡” ʹ͵ ’Žƒ•ƒ‡„”ƒ‡ ƒŽ ‹—Ǧ–”ƒ•Ǧ   ‡”˜‡‰”‘™–Šˆƒ –‘”  ’‘”–‹‰ƒ•‡͵  — Ž‡ƒ””‡ ‡’–‘”Ǧ”‡Žƒ–‡†’”‘–‡‹  ƒ†”‡ƒŽ˜‡‹•ƒ’Ž‹‰  ‘—–‡”‹–‘ Š‘†”‹ƒŽ‡„”ƒ‡ ͳš ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž  ͳ ƒŽ ‹—”‡Ž‡ƒ•‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— •—„—‹–ƒŽ’Šƒͳš Šƒ‡Ž’”‘–‡‹ͳ ƒ ƒʹΪȀ ƒŽ‘†—Ž‹Ǧ†‡’‡†‡–’”‘Ǧ ’Ǥ ’ƒ‰‡ –‡‹‹ƒ•‡  ’Žƒ•ƒƒŽ†‘•–‡”‘‡ ‘ ‡–”ƒ–‹‘ ƒ˜ ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž  ’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•™‹–Š  ‘•‹ ƒŽˆ‡”— •‡‹œ—”‡•ƒ†‡—”‘Ž‘‰‹ ƒ„‘”Ǧ  ‘’Ž‡‡–ƒ”›†‡‘š›”‹„‘— Ž‡‹  ƒŽ‹–‹‡• ƒ ‹†  ’Š‘•’Šƒ–‡„—ˆˆ‡”‡†•ƒŽ‹‡  –Š”‡•Š‘Ž† › Ž‡  ’‘Ž›‡”ƒ•‡ Šƒ‹”‡ƒ –‹‘  Ǧ”ƒ› ‘’—–‡†–‘‘‰”ƒ’Š›   ’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹• ͳ „‡–ƒǦ ƒ–‡‹  ʹ ’Š‘•’Šƒ–‹†›Ž‹‘•‹–‘ŽͶǡͷǦ„‹•’Š‘•Ǧ  ›–‘ Š”‘‡ͶͷͲ ’Šƒ–‡  ͳ †ƒ Š•Š—†Š‘‘Ž‘‰ͳ  ’”‘–‡‹‹ƒ•‡   †‹ƒ ›Ž‰Ž› ‡”‘Ž  ’Š‘•’Š‘Ž‹’ƒ•‡ †„ ƒ–ƒ„ƒ•‡‘ˆ‹‰Ž‡— Ž‡‘–‹†‡‘ŽǦ  ’Žƒ•ƒ”‡‹ƒ –‹˜‹–› ›‘”’Š‹••  ”‡‹Ǧƒ‰‹‘–‡•‹ǦƒŽ†‘•–‡”‘‡   †‡Š›†”‘‡’‹ƒ†”‘•–‡”‘‡ •›•–‡  †‡‘š›”‹„‘— Ž‡‹ ƒ ‹†   ”‡‰—Žƒ–‘”‘ˆ ’”‘–‡‹•‹‰ƒŽ‹‰  ƒ•–•‹ƒ  ”‹„‘— Ž‡‹ ƒ ‹†  ‡–Š›Ž‡‡†‹ƒ‹‡–‡–”ƒƒ ‡–‹ ƒ ‹†  ”‡ƒŽ‘—–‡”‡†—ŽŽƒ”›’‘–ƒ••‹—   ‡œ›‡ǦŽ‹‡†‹—‘•‘”„‡– Šƒ‡Ž ƒ••ƒ› ” ”‹„‘•‘ƒŽ”‹„‘— Ž‡‹ ƒ ‹† ƒ ƒ’‹ ƒŽ‡’‹–Š‡Ž‹ƒŽƒΪ Šƒ‡Ž ”–Ǧ“ ”‡ƒŽ–‹‡“—ƒ–‹–ƒ–‹˜‡’‘Ž›‡”ƒ•‡  ‡†‘’Žƒ•‹ ”‡–‹ —Ž— Šƒ‹”‡ƒ –‹‘  —”‘’‡ƒ‘ ‹‡–›‘ˆƒ”†‹‘Ž‘‰›  •–ƒ†ƒ”†‡””‘”‘ˆ–Š‡‡ƒ   —”‘’‡ƒ‘ ‹‡–›‘ˆ ›’‡”–‡•‹‘  •‹‰Ž‡— Ž‡‘–‹†‡’‘Ž›‘”’Š‹•  —”‘’‡ƒ‹‘ – •–‡”‘‹†‘‰‡‹ ƒ —–‡”‡‰—Žƒ–‘”›  —”‘’‡ ’”‘–‡‹ š š‘‡‰‰”‡‰ƒ–‹‘‘•‘”–‹—  ͳ •–”‘ƒŽ‹–‡”ƒ –‹‘‘Ž‡ —Ž‡ͳ  ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•  •Š‘”––ƒ†‡”‡’‡ƒ–   ‰Ž› ‡”ƒŽ†‡Š›†‡͵Ǧ’Š‘•’Šƒ–‡†‡Š›Ǧ  –”ƒ•‡„”ƒ‡ †”‘‰‡ƒ•‡  ƒ‘‹ ƒŽ–”ƒ•‹‡–”‡ ‡’–‘”’‘Ǧ  ‰”‡‡ˆŽ—‘”‡• ‡–’”‘–‡‹ –‡–‹ƒŽ Šƒ‡Ž  ’”‘–‡‹Ǧ ‘—’Ž‡†‹™ƒ”†Ž›Ǧ”‡ –‹Ǧ  ‹˜‡”•‹–¡–•Ž‹‹—ò••‡Ž†‘”ˆ ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž   œ‘ƒˆƒ• ‹ —Žƒ–ƒ   ‰‘ƒ†‘–”‘’‹Ǧ”‡Ž‡ƒ•‹‰Š‘”‘‡   œ‘ƒ‰Ž‘‡”—Ž‘•ƒ ”‡ ‡’–‘”  œ‘ƒ”‡–‹ —Žƒ”‹•  ‰Ž— ‘ ‘”–‹ ‘‹†Ǧ”‡‡†‹ƒ„Ž‡Š›’‡”Ǧ Ƚͳš ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž ƒŽ†‘•–‡”‘‹• •—„—‹–ƒŽ’Šƒͳš ͵ʹ ͵Ǧ„‡–ƒǦŠ›†”‘š›•–‡”‘‹†Ǧ†‡Š›†”‘Ǧ ‰‡ƒ•‡–›’‡ʹ  ‹‡”‹–‘ Š‘†”‹ƒŽ‡„”ƒ‡ ͵ ‹‘•‹–‘ŽǦͳǡͶǡͷǦ–”‹•’Š‘•’Šƒ–‡

ͻ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ

6 Introduction Š‹•™‘”ƒ††”‡••‡•‰‡‡–‹ ƒ†’Šƒ”ƒ ‘Ž‘‰‹ ƒŽƒ•’‡ –•‘ˆ’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘Ǧ ‹•ȋ Ȍǡ‘‡‘ˆ–Š‡‘™—†‡”Ž›‹‰ ƒ—•‡•‘ˆŠ›’‡”–‡•‹‘ǤŠ‹•”‡“—‹”‡•ƒ—Ǧ †‡”•–ƒ†‹‰‘ˆ–Š‡‘”ƒŽ”‡‰—Žƒ–‹‘‘ˆ„Ž‘‘†’”‡••—”‡ǡ‡•’‡ ‹ƒŽŽ›ƒŽ†‘•–‡”‘‡Š‘‡Ǧ ‘•–ƒ•‹•ǡ ƒ† ‹–• †›•”‡‰—Žƒ–‹‘Ǥ —”–Š‡”‘”‡ǡ „ƒ ‰”‘—† ‹ˆ‘”ƒ–‹‘ ‘ †‹ˆˆ‡”‡– ‘™ ƒ—•‡•‘ˆ ƒ†–Š‡‹”—†‡”Ž›‹‰‰‡‡–‹ •ǡ ‘•‹†‡”‹‰–Š‡’Š›•‹‘Ž‘‰‹ ƒŽƒ† ’ƒ–Š‘’Š›•‹‘Ž‘‰‹ ƒŽ”‘Ž‡•‘ˆ–Š‡‘•–‹’‘”–ƒ–‰‡‡•ǡ‹• ”— ‹ƒŽǤ—––‹‰–Š‡–‘’‹ ‹–‘ ’‡”•’‡ –‹˜‡„›‰ƒ‹‹‰ƒ‘˜‡”˜‹‡™ƒ„‘—––Š‡ —””‡–•–ƒ–‡‘ˆ–Š‡ƒ”–‹‡†‹ ƒŽ ƒ”‡ǡ ‹ˆ‘”ƒ–‹‘‘‡’‹†‡‹‘Ž‘‰›ǡ†‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘’–‹‘•‹•ƒŽ•‘‹’‘”–ƒ–Ǥ ƒ†Ǧ †‹–‹‘ǡƒ”‡˜‹‡™‘ˆ•—‹–ƒ„Ž‡‘†‡Ž•ˆ‘”–Š‡‹˜‡•–‹‰ƒ–‹‘‘ˆ ‹•˜‹–ƒŽˆ‘”–Š‡’—”’‘•‡ ‘ˆ–Š‹•™‘”ǤŽŽ–Š‡•‡ƒ•’‡ –•™‹ŽŽ„‡ ‘˜‡”‡†‹–Š‹•‹–”‘†— –‘”›•‡ –‹‘Ǥ

6.1 Blood pressure and its regulation Š‡ˆ‘” ‡ ‹” —Žƒ–‹‰„Ž‘‘†‡š‡”–•‘–Š‡•—”ˆƒ ‡‘ˆƒ”–‡”‹ƒŽ™ƒŽŽ•‹•”‡ˆ‡””‡†–‘ƒ•„Ž‘‘† ’”‡••—”‡Ǥ –‹•—•—ƒŽŽ›‡ƒ•—”‡†‹ ‰ƒ†‡š’”‡••‡†ƒ••›•–‘Ž‹ ƒ††‹ƒ•–‘Ž‹ „Ž‘‘† ’”‡••—”‡ǡ–Š‡ˆ‘”‡””‡ˆ‡””‹‰–‘–Š‡ƒš‹—’”‡••—”‡†—”‹‰ƒŠ‡ƒ”–„‡ƒ–ƒ†–Š‡ Žƒ––‡””‡’”‡•‡–‹‰–Š‡‹‹—’”‡••—”‡„‡–™‡‡–™‘Š‡ƒ”–„‡ƒ–•ȋ•‡‡‡Ǥ‰ǤͳǡʹȌǤ

Ž‘‘†’”‡••—”‡‹•†‡–‡”‹‡†„›•–”‘‡˜‘Ž—‡ƒ†Š‡ƒ”–”ƒ–‡ǡƒ•™‡ŽŽƒ•”‡•‹•–ƒ ‡Ǥ Š‡Žƒ––‡”‹••–”‘‰Ž›†‡’‡†‡–‘„Ž‘‘†˜‡••‡Ž†‹ƒ‡–‡”ƒ†˜‹• ‘•‹–›‘ˆ–Š‡„Ž‘‘†ͳǤ Š‡•–”‘‡˜‘Ž—‡‹•–Š‡˜‘Ž—‡‘ˆ„Ž‘‘†‡Œ‡ –‡†ˆ”‘–Š‡Š‡ƒ”–†—”‹‰‘‡„‡ƒ–͵Ǥ

6.1.1 Systemic regulation in the normotensive body Ž‘‘†’”‡••—”‡Š‘‡‘•–ƒ•‹• ƒ‘ —”˜‹ƒˆƒ•–ƒ –‹‰‡ Šƒ‹••ƒ†‘”‡•Ž‘™Ž›ƒ –Ǧ ‹‰‘‡•Ǥ‡‡šƒ’Ž‡‘ˆƒ”ƒ’‹†”‡•’‘•‡‡ Šƒ‹•‹•–Š‡„ƒ”‘”‡ˆŽ‡šǡ™Š‹ Š‹•‡†‹Ǧ ƒ–‡†„›•–”‡– Š•‡•‘”•Ž‘ ƒ–‡†‹–Š‡ ƒ”‘–‹†„‘†‹‡•ƒ•™‡ŽŽƒ•–Š‡ƒ‘”–‹ ƒ” ŠǤŠ‡•‡ ”‡ ‡’–‘”• ƒˆˆ‡ – „Ž‘‘† ’”‡••—”‡ –Š”‘—‰Š ”‡‰—Žƒ–‹‘ ‘ˆ •›’ƒ–Š‡–‹  ƒ† ’ƒ”ƒ•›’ƒǦ –Š‡–‹ ƒ –‹˜‹–›ǡƒˆˆ‡ –‹‰˜ƒ•‘ ‘•–”‹ –‹‘ǡŠ‡ƒ”–”ƒ–‡ƒ† ‘–”ƒ –‹Ž‡ˆ‘” ‡ͶǤ

‘”–Š‹•™‘”‡ Šƒ‹••‡š‡”–‹‰‘”‡•—•–ƒ‹‡†‡ˆˆ‡ –•ƒ”‡‘ˆ•’‡ ‹ƒŽ‹–‡”‡•–ǡ‹ ’ƒ”–‹ —Žƒ”–Š‡”‡‹Ǧƒ‰‹‘–‡•‹ǦƒŽ†‘•–‡”‘‡•›•–‡ȋȌǤ

6.1.1.1 Renin-angiotensin-aldosterone system (RAAS) Š‡‹•‘‡‘ˆ–Š‡•Ž‘™‡”ƒ –‹‰‡ Šƒ‹••‘ˆ„Ž‘‘†’”‡••—”‡Š‘‡‘•–ƒ•‹•Ǥ‡‹ ‹••›–Š‡•‹œ‡†ˆ”‘‹–•’”‡ —”•‘”’”‘”‡‹ǡƒ†‹–‹••–‘”‡†‹‰”ƒ—Ž‡•‘ˆŒ—š–ƒ‰Ž‘‡”Ǧ —Žƒ” ‡ŽŽ•ͷǤ —š–ƒ‰Ž‘‡”—Žƒ” ‡ŽŽ•‹–Š‡‹†‡›”‡Ž‡ƒ•‡”‡‹‹”‡•’‘•‡–‘ǣƒȌŽ‘™„Ž‘‘† ’”‡••—”‡†‡–‡ –‡†„›ƒ”‡ƒŽ„ƒ”‘”‡ ‡’–‘”‡ Šƒ‹•ǡ‘•–Ž‹‡Ž›–Š”‘—‰Š”‡˜‡”•ƒŽ‘ˆ ͳͲ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ

Š‹‰Š’”‡••—”‡Ǧ‹†— ‡†•—’’”‡••‹‘ǡ„Ȍ•›’ƒ–Š‡–‹ •‹‰ƒŽ‹‰–Š”‘—‰Šéͳƒ†”‡‡”‰‹  ”‡ ‡’–‘”•ǡƒ† Ȍƒ•ƒ”‡ƒ –‹‘–‘’”‘•–ƒ‰Žƒ†‹•”‡Ž‡ƒ•‡†„›ƒ —Žƒ†‡•ƒ ‡ŽŽ•‘ˆ–Š‡ †‹•–ƒŽ ‘˜‘Ž—–‡†–—„—Ž‡—’‘†‡–‡ –‹‘‘ˆƒ†‡ ”‡ƒ•‡†Ž—‹ƒŽƒΪŽ‘ƒ†ͷȋ ‹‰—”‡ͳȌǤ

‡‹‹•ƒƒ•’ƒ”–›Ž’”‘–‡ƒ•‡ǡ™Š‹ Š ‘˜‡”–•ƒ‰‹‘–‡•‹‘‰‡ǡƒͶͷʹƒ‹‘ƒ ‹†’”‘Ǧ –‡‹•‡ ”‡–‡†‹–‘–Š‡„Ž‘‘†•–”‡ƒ‘•–Ž›„›Ž‹˜‡” ‡ŽŽ•ǡ‹–‘ƒ‰‹‘–‡•‹ ȋ‰ Ȍ͸Ǥ‰ ǡ ƒ†‡ ƒ’‡’–‹†‡ǡ‹• Ž‡ƒ˜‡†‹–‘–Š‡ͺƒ‹‘ƒ ‹†’‡’–‹†‡ƒ‰‹‘–‡•‹ ȋ‰ Ȍ„›–Š‡ ƒ‰‹‘–‡•‹Ǧ ‘˜‡”–‹‰‡œ›‡ȋȌ‡š’”‡••‡†‘–Š‡•—”ˆƒ ‡‘ˆƒ˜ƒ”‹‡–›‘ˆ ‡ŽŽ•ǡ‡Ǥ‰Ǥ ˜ƒ• —Žƒ”‡†‘–Š‡Ž‹ƒŽ ‡ŽŽ•‹–Š‡Ž—‰͸ǡ͹ȋ ‹‰—”‡ͳȌǤ‰ ƒ –•ƒ•ƒ†‹”‡ –˜ƒ•‘ ‘•–”‹ –‘” ȋ ‹‰—”‡ͳȌǡƒˆˆ‡ –‹‰•‘‘–Š—• Ž‡ ‡ŽŽ•‹„Ž‘‘†˜‡••‡Ž•„›„‹†‹‰–‘–Š‡ƒ‰‹‘–‡•‹

”‡ ‡’–‘”ͳȋͳȌǡ ƒ—•‹‰ “Ǧ‡†‹ƒ–‡†ƒ –‹˜ƒ–‹‘‘ˆ’Š‘•’Š‘Ž‹’ƒ•‡ȋȌǡ™Š‹ Š‰‡Ǧ

‡”ƒ–‡•‹‘•‹–‘ŽǦͳǡͶǡͷǦ–”‹•’Š‘•’Šƒ–‡ȋ ͵Ȍƒ††‹ƒ ›Ž‰Ž› ‡”‘Žˆ”‘’Š‘•’Šƒ–‹†›Ž‹‘•‹–‘ŽǦ

ͶǡͷǦ„‹•’Š‘•’Šƒ–‡ ȋ ʹȌǤ Š‹• –Š‡ Ž‡ƒ†• –‘ ƒ ‹‘•‹–‘ŽǦͳǡͶǡͷǦ–”‹•’Š‘•’Šƒ–‡ ȋ ͵ȌǦ†‡Ǧ ’‡†‡–”‹•‡‹ ›–‘’Žƒ•‹ ƒʹΪŽ‡˜‡Ž•ǡ ƒ—•‹‰ ‘–”ƒ –‹‘ǤƒʹΪ‹ˆŽ—š–Š”‘—‰Š ŠƒǦ ‡Ž•‹–Š‡‡„”ƒ‡ ‘–”‹„—–‡•–‘–Šƒ–‡ˆˆ‡ –ͺǤ ƒ††‹–‹‘ǡ‰ ‹ ”‡ƒ•‡•ƒΪƒ† –Š‡”‡ˆ‘”‡™ƒ–‡””‡–‡–‹‘‹–Š‡‹†‡›„›ƒ –‹˜ƒ–‹‰–Š‡ƒΪȀ ΪǦ‡š Šƒ‰‡”‹–Š‡’”‘šǦ

‹ƒŽ–—„—Ž‡•ͻȋ ‹‰—”‡ͳȌǤ –ƒŽ•‘‡†‹ƒ–‡•ƒ‡‰ƒ–‹˜‡ˆ‡‡†„ƒ ‡ Šƒ‹•˜‹ƒͳǡ™Š‹ Š †‹”‡ –Ž›‹Š‹„‹–•”‡‹•‡ ”‡–‹‘ˆ”‘Œ—š–ƒ‰Ž‘‡”—Žƒ” ‡ŽŽ•ͳͲȋ ‹‰—”‡ͳȌǤ‡•‹†‡•–Š‹• ƒ—–‘”‡‰—Žƒ–‘”›‡ˆˆ‡ –ǡ‹Š‹„‹–‹‘ ƒ„‡ƒ Š‹‡˜‡†–Š”‘—‰Šƒ–”‹ƒŽƒ–”‹—”‡–‹ ’‡’Ǧ –‹†‡ȋȌǡƒŠ‘”‘‡•‡ ”‡–‡†ˆ”‘–Š‡Š‡ƒ”–—’‘†‡–‡ –‹‘‘ˆŽ‘™„Ž‘‘†˜‘Ž—‡ǡ ™Š‹ Š‹ǤƒǤ‘†—Žƒ–‡••‡ ”‡–‹‘‘ˆ”‡‹ͳͳȋƒŽ•‘•‡‡͸ǤͳǤʹǤͳǤͶȌǤ

‘”‡‘˜‡”ǡ‰ •–‹—Žƒ–‡•–Š‡ƒ†”‡ƒŽ‰Žƒ†˜‹ƒͳ„‹†‹‰–‘’”‘†— ‡–Š‡‹‡”ƒŽǦ ‘ ‘”–‹ ‘‹†Š‘”‘‡ƒŽ†‘•–‡”‘‡ǡ™Š‹ Š–Š‡’”‘‘–‡•”‡–‡–‹‘‘ˆƒΪƒ†–Š—•™ƒ–‡” ‹–‘–Š‡„Ž‘‘†ƒ•™‡ŽŽƒ•Ϊ‡š ”‡–‹‘‹–‘–Š‡—”‹‡‹–Š‡ ‘ŽŽ‡ –‹‰†— –ƒ†Žƒ–‡†‹•–ƒŽ ‘˜‘Ž—–‡†–—„—Ž‡‘ˆ–Š‡‹†‡›ͳʹȋ ‹‰—”‡ͳȌǤ‹ƒ‹–‡”ƒ –‹‘™‹–Š–Š‡‹‡”ƒŽ‘ ‘”–‹ ‘‹† ”‡ ‡’–‘”ǡƒŽ†‘•–‡”‘‡‹†— ‡•‡š’”‡••‹‘ƒ†ƒ –‹˜ƒ–‹‘‘ˆ„ƒ•‘Žƒ–‡”ƒŽƒΪȀΪǦƒ•‡ ƒ•™‡ŽŽƒ•—’”‡‰—Žƒ–‹‘‘ˆ–Š‡ƒ’‹ ƒŽ‡’‹–Š‡Ž‹ƒŽƒΪ Šƒ‡ŽȋƒȌǡ–Š—•’”‘‘–‹‰–Š‡ ”‡ƒ„•‘”’–‹‘‘ˆƒΪ‹–‘–Š‡„Ž‘‘†•–”‡ƒ™‹–Š™ƒ–‡””‡ƒ„•‘”’–‹‘ƒ•ƒ ‘’—Ž•‘”›”‡Ǧ •—Ž–†—‡–‘‘•‘•‹•ͳʹȂͳͶǤ ƒ††‹–‹‘ǡƒŽ†‘•–‡”‘‡‹ ”‡ƒ•‡•–Š‡‡š’”‡••‹‘‘ˆ•‡”—ƒ† ‰Ž— ‘ ‘”–‹ ‘‹†Ǧ‹†— ‡†‹ƒ•‡ ͳǡ™Š‹ Šǡ„‡•‹†‡•ƒ –‹˜ƒ–‹‰–Š‡ƒΪȀΪǦ’—’ƒ† ƒǡƒŽ•‘‹ ”‡ƒ•‡•‡„”ƒ‡ƒ„—†ƒ ‡‘ˆ–Š‡”‡ƒŽ‘—–‡”‡†—ŽŽƒ”›’‘–ƒ••‹— Šƒ‡ŽȋȌƒ†–Š—•ˆƒ ‹Ž‹–ƒ–‡•Ϊ Ž‡ƒ”ƒ ‡‹–‘–Š‡—”‹‡ͳʹǡͳͶǡͳͷǤ —”–Š‡”‘”‡ǡ  ͳ’Žƒ›•ƒ”‘Ž‡‹—’”‡‰—Žƒ–‹‘‘ˆ•‘†‹— ŠŽ‘”‹†‡•›’‘”–‡”ȋȌƒ –‹˜‹–›ǡƒ–”ƒ•Ǧ ’‘”–‡”™Š‘•‡ƒ –‹˜‹–›ƒ†‡š’”‡••‹‘Šƒ˜‡„‡‡Ž‹‡†–‘ƒŽ†‘•–‡”‘‡•–‹—Žƒ–‹‘‹

ͳͳ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ –Š‡†‹•–ƒŽ ‘˜‘Ž—–‡†–—„—Ž‡ǡ–Š—•‹ ”‡ƒ•‹‰–Š‡‹–”ƒ ‡ŽŽ—Žƒ”ƒΪ ‘ ‡–”ƒ–‹‘ˆ‘ŽǦ Ž‘™‡†„›”‡ƒ„•‘”’–‹‘‹–‘–Š‡„Ž‘‘†•–”‡ƒ„›ƒΪȀΪǦƒ•‡ͳ͸ȂͳͺǤ‘”‡†‡–ƒ‹Ž‡† †‡• ”‹’–‹‘‘ˆƒŽ†‘•–‡”‘‡•‡ ”‡–‹‘‡†‹ƒ–‡†„›ƒ”ƒ‰‡‘ˆ•–‹—Ž‹ƒ•™‡ŽŽƒ‘”‡‡šǦ –‡•‹˜‡‹•‹‰Š–‹–‘–Š‡—†‡”Ž›‹‰‘Ž‡ —Žƒ”‡ Šƒ‹••™‹ŽŽ„‡’”‘˜‹†‡†‹•‡ –‹‘ ͸ǤͳǤʹǤ

—”–Š‡”‘”‡ǡ‰ •–‹—Žƒ–‡•–Š‡’‹–—‹–ƒ”›‰Žƒ†–‘”‡Ž‡ƒ•‡–Š‡ƒ–‹Ǧ†‹—”‡–‹ Š‘”‘‡ ȋ ȌǡƒŽ•‘ ƒŽŽ‡†˜ƒ•‘’”‡••‹Ǥ ‹•ƒ˜ƒ•‘ ‘•–”‹ –‘”Š‘”‘‡ǡ™Š‹ Š’”‘‘–‡•™ƒǦ –‡””‡–‡–‹‘‹–Š‡‹†‡›–Š”‘—‰Š‹•‡”–‹‘‘ˆƒ“—ƒ’‘”‹ʹ™ƒ–‡” Šƒ‡Ž•‹–‘–Š‡ ƒ’‹ ƒŽ‡„”ƒ‡•‘ˆ‡’‹–Š‡Ž‹ƒŽ ‡ŽŽ•‹–Š‡ ‘ŽŽ‡ –‹‰†— –Ǥ††‹–‹‘ƒŽŽ›ǡ ‡†‹ƒ–‡• ‹ ”‡ƒ•‡†ƒ“—ƒ’‘”‹ʹ–”ƒ• ”‹’–‹‘ͳͻǡʹͲȋ ‹‰—”‡ͳȌǤ

‘•—ƒ”‹œ‡ǡ–Š‡ƒˆˆ‡ –•„Ž‘‘†’”‡••—”‡„›”‡‰—Žƒ–‹‘‘ˆ‘˜‡”ƒŽŽ˜ƒ• —Žƒ””‡Ǧ •‹•–ƒ ‡–Š”‘—‰Š˜ƒ•‘ ‘•–”‹ –‹‘ƒ†„› ‘–”‘ŽŽ‹‰•–”‘‡˜‘Ž—‡–Š‘—‰Š”‡–‡–‹‘ ‘ˆ™ƒ–‡”ǡ‡‹–Š‡”†‹”‡ –Ž›‘”‹†‹”‡ –Ž›ƒ•ƒ•‹†‡‡ˆˆ‡ –‘ˆƒΪ”‡–‡–‹‘Ǥ ƒ††‹–‹‘ǡ‹– ’”‘˜‹†‡•ƒ’‘™‡”ˆ—Žƒ—–‘”‡‰—Žƒ–‘”›‡ Šƒ‹•–Š”‘—‰Š‹Š‹„‹–‹‘‘ˆ”‡‹”‡Ž‡ƒ•‡„› ‰ Ǥ

6.1.2 Molecular mechanisms of aldosterone production on cellular level Š‡ƒ†”‡ƒŽ‰Žƒ†‹••–”— –—”‡†‹–‘ƒ‹‡”‡†—ŽŽƒƒ†ƒ‘—–‡” ‘”–‡šǡ™Š‹ Š‹• †‹˜‹†‡†‹–‘–Š”‡‡œ‘‡•ȋˆ”‘–Š‡ ‡–‡”‘—–™ƒ”†•Ȍǣ–Š‡œ‘ƒ”‡–‹ —Žƒ”‹•ȋȌǡœ‘ƒ ˆƒ• ‹ —Žƒ–ƒȋ Ȍƒ†œ‘ƒ‰Ž‘‡”—Ž‘•ƒȋ ȌʹͳǤŠ‡œ‘‡•‘ˆ–Š‡ƒ†”‡ƒŽ ‘”–‡šƒ”‡‹Ǧ ˜‘Ž˜‡†‹•–‡”‘‹†‘‰‡‡•‹•ǣŠ‡‰Ž— ‘ ‘”–‹ ‘‹† ‘”–‹•‘Ž‹••›–Š‡•‹œ‡†‹–Š‡ ǡ™Š‹Ž‡ –Š‡Š—ƒ’”‘†— ‡•’”‡ —”•‘”ƒ†”‘‰‡•ǡŽ‹‡†‡Š›†”‘‡’‹ƒ†”‘•–‡”‘‡ȋ Ȍ ƒ†ƒ†”‘•–‡‡†‹‘‡Ǥ‡˜‡”–Š‡Ž‡••ǡ ‡ŽŽ•ƒ”‡ƒŽ•‘ƒ„Ž‡–‘’”‘†— ‡ ‘”–‹•‘ŽǤŠ‡‹Ǧ ‡”ƒŽ‘ ‘”–‹ ‘‹†ƒŽ†‘•–‡”‘‡‹•’”‘†— ‡†‹  ‡ŽŽ•ʹͳǡʹʹǤ

6.1.2.1 Modulators of aldosterone production Š‡‘•–‹’‘”–ƒ–‘†—Žƒ–‘”•‘ˆƒŽ†‘•–‡”‘‡•‡ ”‡–‹‘—†‡”’Š›•‹‘Ž‘‰‹ ƒŽ ‘†‹Ǧ –‹‘•ƒ”‡‰ ǡƒ†”‡‘ ‘”–‹ ‘–”‘’‹ Š‘”‘‡ȋ Ȍǡƒ•™‡ŽŽƒ•‹ ”‡ƒ•‡†‡š–”ƒ ‡ŽŽ—Ǧ Žƒ”Ϊ ‘ ‡–”ƒ–‹‘ƒ –‹‰ƒ•’‘•‹–‹˜‡•–‹—Ž‹ǡ™Š‹Ž‡ƒ –•ƒ•ƒ‹Š‹„‹–‘”ȋ ‘’ƒ”‡ ‡Ǥ‰Ǥʹ͵ȌǤ



ͳʹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ



&ŝŐƵƌĞϭ͘dŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶͲĂůĚŽƐƚĞƌŽŶĞƐLJƐƚĞŵ;Z^Ϳ͘ŶŐŝŽƚĞŶƐŝŶŽŐĞŶŝƐƌĞůĞĂƐĞĚďLJĐĞůůƐŽĨƚŚĞůŝǀĞƌ͘ /ƚŝƐĐŽŶǀĞƌƚĞĚƚŽĂŶŐŝŽƚĞŶƐŝŶ/ďLJƌĞŶŝŶ͘ZĞŶŝŶƌĞůĞĂƐĞĨƌŽŵƚŚĞũƵdžƚĂŐůŽŵĞƌƵůĂƌĐĞůůƐŽĨƚŚĞŬŝĚŶĞLJŝƐƉƌŽͲ ŵŽƚĞĚďLJůŽǁďůŽŽĚƉƌĞƐƐƵƌĞ͕ĂůŽǁůƵŵŝŶĂůEĂнĐŽŶĐĞŶƚƌĂƚŝŽŶĂŶĚƐLJŵƉĂƚŚĞƚŝĐƐŝŐŶĂůŝŶŐ͘ŶŐŝŽƚĞŶƐŝŶ/ŝƐ ĐŽŶǀĞƌƚĞĚƚŽĂŶŐŝŽƚĞŶƐŝŶ//ďLJĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƚŝŶŐĞŶnjLJŵĞ;ͿĨŽƵŶĚĞ͘Ő͘ŝŶƚŚĞůƵŶŐ͘ŶŐŝŽƚĞŶƐŝŶ// ƉƌŽŵŽƚĞƐǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶĂŶĚEĂнͬǁĂƚĞƌƌĞƚĞŶƚŝŽŶŝŶƚŚĞŬŝĚŶĞLJĂƐǁĞůůĂƐƐĞĐƌĞƚŝŽŶŽĨĂůĚŽƐƚĞƌŽŶĞĨƌŽŵ ƚŚĞĂĚƌĞŶĂůŐůĂŶĚĂŶĚƌĞůĞĂƐĞŽĨǀĂƐŽƉƌĞƐƐŝŶĨƌŽŵƚŚĞƉŝƚƵŝƚĂƌLJ͘dŚĞƐĞŚŽƌŵŽŶĞƐƉƌŽŵŽƚĞǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶ͕ ĂƐǁĞůůĂƐEĂнĂŶĚͬŽƌǁĂƚĞƌƌĞƚĞŶƚŝŽŶ͘dŚĞƐĞĞĨĨĞĐƚƐŵĞĚŝĂƚĞĚďLJĂŶŐŝŽƚĞŶƐŝŶ//ƵůƚŝŵĂƚĞůLJůĞĂĚƚŽĂŶŝŶĐƌĞĂƐĞ ŝŶďůŽŽĚƉƌĞƐƐƵƌĞ͘&ƵƌƚŚĞƌŵŽƌĞ͕ĂŶŐŝŽƚĞŶƐŝŶ//ͲŵĞĚŝĂƚĞĚŝŶŚŝďŝƚŝŽŶŽĨƌĞŶŝŶƌĞůĞĂƐĞĐŽŶƐƚŝƚƵƚĞƐĂŶĞŐĂƚŝǀĞ ĨĞĞĚďĂĐŬ ŵĞĐŚĂŶŝƐŵ ;ĐŽŵƉĂƌĞ ƐĞĐƚŝŽŶ ϲ͘ϭ͘ϭ͘ϭͿ͘ ĚĂƉƚĞĚ ĨƌŽŵ ƵƚƚĂ͕ ^ƂĚĞƌŬǀŝƐƚ ĂŶĚ 'ƌŝŵŵ͕ ϮϬϭϲϮϰ͘ 

6.1.2.1.1Angiotensin II ‰ ‡†‹ƒ–‡•‹–•‡ˆˆ‡ –•˜‹ƒ„‹†‹‰–‘ ’”‘–‡‹Ǧ ‘—’Ž‡†ƒ‰‹‘–‡•‹”‡ ‡’–‘”•ǡ‘•–

‹’‘”–ƒ–Ž›ͳƒ†ʹǤ‘–Šͳƒ†ʹƒ”‡‡š’”‡••‡†‹–Š‡Š—ƒƒ†”‡ƒŽ‰Žƒ†Ǥ

Š‹Ž‡ͳ‹•ƒ‹Ž›‡š’”‡••‡†‹–Š‡ ǡʹ‹• Š‹‡ˆŽ›‡š’”‡••‡†‹–Š‡‡†—ŽŽƒǡ„—–‹–

ƒƒŽ•‘„‡†‡–‡ –‡†‹–Š‡ ʹͷǤ–Š‡‘‡Šƒ†ǡͳƒ –‹˜ƒ–‹‘’”‘‘–‡•ƒŽ†‘•–‡”‘‡

’”‘†— –‹‘ƒ† ‡ŽŽ‰”‘™–Šƒ•™‡ŽŽƒ•’”‘Ž‹ˆ‡”ƒ–‹‘ʹ͸ǤͳǦ‡†‹ƒ–‡†‰”‘™–ŠǦ’”‘‘–‹‰ ‡ˆˆ‡ –•Šƒ˜‡„‡‡†‡–‡ –‡†‹ƒ†”‡ƒŽ ‡ŽŽ•ǡ‹ Ž—†‹‰–Š‡ ʹ͹ȂʹͻǤ–Š‡‘–Š‡”Šƒ†ǡ

„‹†‹‰–‘ʹ‹Š‹„‹–• ‡ŽŽ‰”‘™–Šƒ†•–‹—Žƒ–‡•ƒ’‘’–‘•‹•ƒ†Šƒ•„‡‡•—‰‰‡•–‡†–‘ ’Žƒ›ƒ”‘Ž‡‹ˆ‡–ƒŽ†‡˜‡Ž‘’‡–ƒ†–‹••—‡”‡‰‡‡”ƒ–‹‘ǡ•‹ ‡‹–•‡š’”‡••‹‘‹•‡Ž‡˜ƒ–‡†

—†‡”–Š‡•‡ ‹” —•–ƒ ‡•ʹ͸ǡ͵ͲǤ –Š‡Š—ƒƒ†”‡ƒŽǡʹ†‹•–”‹„—–‹‘†‹ˆˆ‡”•„‡–™‡‡ ˆ‡–ƒŽƒ†ƒ†—Ž–‰Žƒ†•ǣŠ‹Ž‡‹ƒ†—Ž–•ǡ‹–‹•’”‡†‘‹ƒ–Ž›‡š’”‡••‡†‹–Š‡‡†—ŽŽƒǡ‹– ‹•‡š’”‡••‡†–Š”‘—‰Š‘—––Š‡Š—ƒˆ‡–ƒŽƒ†”‡ƒŽ‰Žƒ†͵ͳǤ

Š‡‡ˆˆ‡ –•‘ˆͳ„‹†‹‰‹–Š‡  ‡ŽŽƒ”‡‡†‹ƒ–‡†„›–Š‡Š‡–‡”‘–”‹‡”‹  ’”‘–‡‹•

‹ƒ† “ǤŠ‡› ƒ—•‡‹Š‹„‹–‹‘‘ˆƒ†‡›Ž›Ž › Žƒ•‡ƒ†ƒˆˆ‡ –˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ʹ͵ǡʹ͸ǡ͵ʹȂ͵ͶǤŠ‡›ƒŽ•‘ƒ –‹˜ƒ–‡’Š‘•’Š‘Ž‹’ƒ•‡ȋȌǡ”‡•—Ž–‹‰‹ˆ‘”ƒ–‹‘‘ˆ

ͳ͵ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ

͵ƒ††‹ƒ ›Ž‰Ž› ‡”‘Žȋ Ȍʹ͵ǡʹ͸ǡ͵ͷǡ͵͸Ǥ ‘”ƒ–‹‘‘ˆ ͵”‡•—Ž–•‹ƒʹΪ”‡Ž‡ƒ•‡ˆ”‘‹Ǧ

–”ƒ ‡ŽŽ—Žƒ”•–‘”‡•–Š”‘—‰Š„‹†‹‰–‘‹‘•‹–‘ŽǦ͵Ǧ’Š‘•’Šƒ–‡”‡ ‡’–‘”•ȋ ͵Ȍˆ‘—†‘ ‡†‘’Žƒ•‹ ”‡–‹ —Ž—ȋȌ˜‡•‹ Ž‡‡„”ƒ‡•™‹–ŠŽ‹‰Š–ƒ––ƒ Š‡––‘–Š‡’Žƒ•ƒ ‡„”ƒ‡‹ƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽ•ʹ͵ǡ͵͹Ȃ͵ͻǤ‡’Ž‡–‹‘‘ˆ‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪ•–‘”‡•Ž‡ƒ†•–‘ ƒʹΪ‹ˆŽ—šˆ”‘–Š‡‡š–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡ƒ†‡š’”‡••‹‘‘ˆ’”‘–‡‹•–Š‘—‰Š––‘„‡‹Ǧ ˜‘Ž˜‡†‹–Š‹•’”‘ ‡••ǡ‹Ǥ‡Ǥ•–”‘ƒŽ‹–‡”ƒ –‹‘‘Ž‡ —Ž‡ͳȋ ͳȌǡ ƒŽ ‹—”‡Ž‡ƒ•‡Ǧ ƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Ž’”‘–‡‹ͳȋ ͳȌƒ† ƒ‘‹ ƒŽ–”ƒ•‹‡–”‡ ‡’–‘”’‘–‡–‹ƒŽ Šƒ‡Ž•ȋȌǡŠƒ•„‡‡”‡’‘”–‡†‹–Š‡ ʹͻͷƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ʹ͵ǡͶͲǤ

‰ ƒŽ•‘‹†— ‡•ƒʹΪ‹ˆŽ—šˆ”‘‡š–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡˜‹ƒ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡†ƒʹΪ Šƒ‡Ž•ǡ ™Š‹ Š”‡“—‹”‡•†‡’‘Žƒ”‹œƒ–‹‘‘ˆ–Š‡ ‡ŽŽ‡„”ƒ‡Ǥ‡’‘Žƒ”‹œƒ–‹‘‹•ƒ Š‹‡˜‡†„›Ǧ ‰ Ǧ‹†— ‡†‹Š‹„‹–‹‘‘ˆ–Š‡ƒΪȀΪǦƒ•‡ǡ‹ ”‡ƒ•‹‰‘’‡’”‘„ƒ„‹Ž‹–›‘ˆ‘Ǧ•‡Ž‡ Ǧ –‹˜‡ ƒ–‹‘ Šƒ‡Ž•ƒ†‹Š‹„‹–‹‘‘ˆΪ ‘†— –ƒ ‡–Š”‘—‰Š Šƒ‡Ž•ƒ –‹˜‡ƒ–”‡•–Ǧ ‹‰’‘–‡–‹ƒŽǤ Š‹„‹–‹‘‘ˆ Šƒ‡Ž•„›‰ Šƒ•„‡‡•—‰‰‡•–‡†–‘„‡ƒ‹Ǧ ’‘”–ƒ– ‘–”‹„—–‘”–‘–Š‡Žƒ––‡”‡ˆˆ‡ –ʹ͵ǡͶͳȂͶ͵Ǥ

‘†—Žƒ–‹‘‘ˆ”‡ ‡’–‘”Ǧ‡†‹ƒ–‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ ƒ‘ —”˜‹ƒ•‡•‹–‹œƒ–‹‘ ‘”†‡•‡•‹–‹œƒ–‹‘ǡ™Š‹ Š ƒ„‡ƒ Š‹‡˜‡†˜‹ƒ”‡‰—Žƒ–‹‘‘ˆ”‡ ‡’–‘”ƒ„—†ƒ ‡‘–Š‡ ‡ŽŽ•—”ˆƒ ‡‘” ‘–”‘ŽŽ‹‰–Š‡•‡•‹–‹˜‹–›‘ˆ–Š‡”‡ ‡’–‘”‹–•‡Žˆʹ͵Ǥ‘–Š‡ˆˆ‡ –•Šƒ˜‡„‡‡

‘„•‡”˜‡†™‹–Š”‡‰ƒ”†–‘–Š‡ͳ”‡ ‡’–‘”ͶͶȂͶ͹Ǥ ‘™‡˜‡”ǡin vivoǡ‰ ’”‡‡š’‘•—”‡ǡƒ• ™‡ŽŽƒ••‘†‹—†‡’Ž‡–‹‘ƒ’’‡ƒ”–‘‹ ”‡ƒ•‡–Š‡ƒŽ†‘•–‡”‘‡”‡•’‘•‡–‘‰ ͶͺǡͶͻǤŠ‹• Šƒ•„‡‡•—‰‰‡•–‡†–‘„‡ƒ‹†‹”‡ –‡ˆˆ‡ ––Šƒ–”‡“—‹”‡•–Š‡’”‡•‡ ‡‘ˆ‘–Š‡” ‹” —Žƒ–Ǧ ‹‰Š‘”‘‡•ǡŽ‹‡ ʹ͵Ǥ

6.1.2.1.2Adrenocorticotropic hormone  •–‹—Žƒ–‡•–Š‡  ‡ŽŽ„›„‹†‹‰–‘–Š‡‡Žƒ‘ ‘”–‹ʹ”‡ ‡’–‘”ȋʹȌǡ™Š‹ Š ‹• ’”‘–‡‹Ǧ ‘—’Ž‡†ʹʹǤ ’”‘–‡‹•–Š‡‡†‹ƒ–‡ƒ –‹˜ƒ–‹‘‘ˆƒ†‡›Ž›Ž › Žƒ•‡ǡ–Š‡”‡„› —’”‡‰—Žƒ–‹‰’”‘†— –‹‘‘ˆ ʹʹǡͷͲǤ Ǧ‹†— ‡† ’”‘†— –‹‘ ƒ„‡‹Š‹„Ǧ ‹–‡†„›‰ ‹  ‡ŽŽ•ͷͳǤ ƒ††‹–‹‘–‘‹ ”‡ƒ•‹‰ ’”‘†— –‹‘ǡ „‹†‹‰–‘ ʹŽ‡ƒ†•–‘†‡’‘Žƒ”‹œƒ–‹‘ǡ’ƒ”–Ž›ƒ––”‹„—–‡†–‘‹Š‹„‹–‹‘‘ˆΪ ‘†— –ƒ ‡ǡƒ† –Š—• ƒ—•‡•ƒʹΪ‹ˆŽ—š–Š”‘—‰Šƒ –‹˜ƒ–‹‘‘ˆǦ–›’‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǡ ™Š‹ Š ƒ„‡‡†‹ƒ–‡†„› ƒ†’”‘–‡‹‹ƒ•‡ȋȌʹʹǡͷʹȂͷͶǤ Ǧ†‡’‡†‡– ˆ‘”ƒ–‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ ƒ’’‡ƒ”–‘„‡‰”‡ƒ–Ž›”‡Ž›‹‰‘ ƒʹΪ”‡ˆʹ͵ǡͷͷǤ –‡”‡•–‹‰Ž›ǡ •–‹—Žƒ–‹‘Šƒ•„‡‡•Š‘™–‘‹†— ‡ƒ•Š‘”–Ǧ–‡”‹Ǧ ”‡ƒ•‡‹ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•ǡ„—–in vivo‡š’‡”‹‡–•‹”ƒ–•ƒ†Š—ƒ••—‰‰‡•––Šƒ–‹– ƒ”‡†— ‡ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡Ž‘‰–‡”ͷ͸ȂͷͺǤ

ͳͶ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ 6.1.2.1.3Potassium  ”‡ƒ•‹‰ ‡š–”ƒ ‡ŽŽ—Žƒ” Ϊ ‘ ‡–”ƒ–‹‘Ž‡ƒ†•–‘‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ǤŠ‹• ƒ—•‡•ƒʹΪ‹ˆŽ—šˆ”‘‡š–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡–Š”‘—‰Š˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǡ ‰‡‡”ƒ–‹‰ƒ‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪ•‹‰ƒŽʹ͵ǡͷͻǡ͸ͲǤŠ‡Š‹‰ŠŽ›•‡•‹–‹˜‡”‡•’‘•‡‘ˆ  ‡ŽŽ• –‘ Šƒ‰‡•‹–Š‡‡š–”ƒ ‡ŽŽ—Žƒ”Ϊ ‘ ‡–”ƒ–‹‘ƒ’’‡ƒ”•–‘„‡„ƒ•‡†ƒ‹Ž›‘–Š‡‹” Žƒ”‰‡Ϊ ‘†— –‹˜‹–›ǡƒ•™‡ŽŽƒ•‘–Š‡‹˜‘Ž˜‡‡–‘ˆŽ‘™˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— ŠƒǦ ‡Ž•ǡ™Š‹ Š‰‡‡”ƒ–‡‘• ‹ŽŽƒ–‹‘•‹–Š‡‡„”ƒ‡’‘–‡–‹ƒŽ͸ͳȂ͸͵Ǥ

6.1.2.1.4Atrial natriuretic peptide ǡƒ‡‰ƒ–‹˜‡”‡‰—Žƒ–‘”‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǡ‹ ”‡ƒ•‡•Ϊ ‘†— –ƒ ‡‘ˆ–Š‡ ‡ŽŽ–Š”‘—‰Šƒ –‹˜ƒ–‹‘‘ˆ’‘–ƒ••‹— Šƒ‡Ž•Ǥ ‘”†‹‰Ž›ǡ•‡ —”‡•‡„”ƒ‡Š›Ǧ ’‡”’‘Žƒ”‹œƒ–‹‘Ǥ –ˆ—”–Š‡”‘’’‘•‡•ƒʹΪ•‹‰ƒŽ‹‰„›‹Š‹„‹–‹‘‘ˆǦ–›’‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ʹ͵ǡ͸ͶȂ͸͸Ǥ

6.1.2.2 Enzymes involved in aldosterone production and their regulation ƒʹΪ•‹‰ƒŽ‹‰‹•ƒ ‘‘’”‡”‡“—‹•‹–‡‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹†— ‡†„›†‹ˆˆ‡”‡– •–‹—Ž‹Ǥ  ‡ŽŽ•†‘‘–Šƒ˜‡Š‘”‘‡•–‘”‡•„—–’”‘†— ‡•–‡”‘‹†•—’‘•–‹—Žƒ–‹‘ʹ͵Ǥ Š‡•–‡’•‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ƒ†”‡ƒŽ ƒ”‡†‡’‹ –‡†‹ ‹‰—”‡ʹǤŠ‡ ‰‡‡”ƒŽ”ƒ–‡ǦŽ‹‹–‹‰•–‡’‘ˆ•–‡”‘‹†‘‰‡‡•‹•‹•–Š‡ˆ‘”ƒ–‹‘‘ˆ’”‡‰‡‘Ž‘‡ˆ”‘ Š‘Ž‡•–‡”‘ŽǤŠ‹•”‡“—‹”‡•–”ƒ•’‘”–‘ˆ Š‘Ž‡•–‡”‘Žˆ”‘–Š‡‘—–‡”‹–‘ Š‘†”‹ƒŽ‡Ǧ „”ƒ‡–‘–Š‡‹‡”‹–‘ Š‘†”‹ƒŽ‡„”ƒ‡ǡ™Š‹ Š‹•‡†‹ƒ–‡†„›–Š‡•–‡”‘‹†‘‰‡‹  ƒ —–‡”‡‰—Žƒ–‘”›’”‘–‡‹ȋ–Ȍʹ͵Ǥš’”‡••‹‘ǡƒ•™‡ŽŽƒ•ƒ –‹˜ƒ–‹‰’Š‘•’Š‘”›Žƒ–‹‘‘ˆ –ƒ”‡’”‘‘–‡†„› ǡ‰ ƒ†Ϊǡ™Š‹Ž‡”‡†— ‡•StAR–”ƒ• ”‹’–‹‘ʹ͵ǡ͸͹Ȃ ͹ͲǤ

6.1.2.2.1Aldosterone synthase (CYP11B2) Ž†‘•–‡”‘‡•›–Šƒ•‡ȋͳͳʹȌ ƒ–ƒŽ›œ‡•–Š‡•‡ ‘†”ƒ–‡ǦŽ‹‹–‹‰•–‡’‹ƒŽ†‘•–‡Ǧ ”‘‡’”‘†— –‹‘ȋ ‘’ƒ”‡͹ͳȌǤCYP11B2‹•‡š’”‡••‡†‹–Š‡ ƒŽ‘‡ǡ–Š—•Ž‹‹–‹‰ƒŽǦ †‘•–‡”‘‡’”‘†— –‹‘–‘–Š‹•”‡‰‹‘‘ˆ–Š‡ƒ†”‡ƒŽ ‘”–‡šͷ͸Ǥ –Š‡ƒ†”‡‘ ‘”–‹ ƒŽ ƒ”Ǧ ‹‘ƒ ‡ŽŽŽ‹‡ ʹͻͷǡ•–‹—Žƒ–‹‘™‹–Š‰ ƒ†ΪŽ‡ƒ†•–‘‹ ”‡ƒ•‡†CYP11B2‡šǦ ’”‡••‹‘͹ʹǡ͹͵ȋ ‘’ƒ”‡ ‹‰—”‡ͷƒ†ˆ‘”ƒ• Š‡ƒ–‹ †‡’‹ –‹‘‘ˆ‰ Ǧ‡†‹ƒ–‡† ‡ˆˆ‡ –•ȌǤ †— –‹‘„›„‘–Š•–‹—Ž‹ƒ’’‡ƒ”–‘ˆ‘ŽŽ‘™†‹ˆˆ‡”‡–‹‡–‹ •ǣ’‘•–‹—Žƒ–‹‘ ™‹–ŠͳͲͲ‰ ǡCYP11B2‡š’”‡••‹‘‹ ʹͻͷ ‡ŽŽ•’‡ƒ•ƒˆ–‡”ƒ”‘—†ͳʹŠƒ† –Š‡†‡ Ž‹‡•ƒ‰ƒ‹ǡ™Š‹Ž‡—’‘•–‹—Žƒ–‹‘™‹–ŠͳͲŽǡ—’”‡‰—Žƒ–‹‘‘ˆ‡š’”‡•Ǧ •‹‘™ƒ••–‹ŽŽ‘„•‡”˜‡†ƒˆ–‡”ͶʹŠ͹ͶǤ

ͳͷ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ƒʹΪǦ‘„‹Ž‹œ‹‰ƒ‰‡–•Šƒ˜‡„‡‡•Š‘™–‘‹ ”‡ƒ•‡‡š’”‡••‹‘‘ˆ–Š‡‡ ‘†‹‰‰‡‡ CYP11B2ǡƒ‡ˆˆ‡ ––Šƒ–‹•‡†‹ƒ–‡†„›ƒʹΪǡ ƒŽ‘†—Ž‹ƒ†ˆ‹ƒŽŽ›ƒʹΪȀ ƒŽ‘†—Ž‹Ǧ †‡’‡†‡–’”‘–‡‹‹ƒ•‡ ȋƒ Ȍǡƒ†–‘ƒŽ‡••‡”‡š–‡–ƒ ͹ͷȂ͹͹Ǥ

ƒ ‹‰Š–ƒ –‹˜ƒ–‡–”ƒ• ”‹’–‹‘ˆƒ –‘”•–Šƒ–„‹†–‘Ǧ‡Ž‡‡–•‹–Š‡CYP11B2 ’”‘‘–‡””‡‰‹‘–Š”‘—‰Š’Š‘•’Š‘”›Žƒ–‹‘Ǥ ‘™‡˜‡”ǡ‘–Š‡””‡‰—Žƒ–‘”›‡Ž‡‡–•ƒŽ•‘ ’Žƒ›ƒ”‘Ž‡ȋ†Ǧͷǡ†ǦͶƒ†ǦͳȌͷ͸ǡ͹͵ǡ͹ͷǡ͹͸ǡ͹ͺǡ͹ͻǤŠ‹Ž‡‘˜‡”‡š’”‡••‹‘‘ˆ ƒ† ͳȋ„‹†‹‰„‘–Š†Ǧͷƒ†ǦͳȌ‹ ”‡ƒ•‡CYP11B2”‡’‘”–‡”‡š’”‡••‹‘ǡ ͳ ȋ„‹†‹‰–‘†ǦͶȌ†‘‡•‘–ƒ’’‡ƒ”–‘„‡ƒƒŒ‘””‡‰—Žƒ–‘”ǡ„—–”‡’‘”–•‘‹–•‡ˆˆ‡ –• ˜ƒ”›͹ͺǡͺͲȂͺʹΎǤ–Š‡”•–‡”‘‹†‘‰‡‹ ‡œ›‡•–Šƒ–ƒ”‡—’”‡‰—Žƒ–‡†„› –”ƒ• ”‹’–‹‘ ˆƒ –‘”•ƒ”‡ ͵ʹƒ†ʹͳȋ‡ ‘†‹‰͵Ǧ„‡–ƒǦŠ›†”‘š›•–‡”‘‹†Ǧ†‡Š›†”‘‰‡ƒ•‡–›’‡ ʹƒ†ʹͳǦŠ›†”‘š›Žƒ•‡ǡ”‡•’‡ –‹˜‡Ž›Ȍͺ͵Ǥ

”‘–‡‹‹ƒ•‡ȋȌƒ’’‡ƒ”•–‘‹Š‹„‹–CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— Ǧ –‹‘ʹ͵ǡͺʹǡͺͶǤ ‘™‡˜‡”ǡ’”‘–‡‹‹ƒ•‡ȋȌǡƒ’‘•‹–‹˜‡”‡‰—Žƒ–‘”‘ˆCYP11B2‡š’”‡•Ǧ •‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǡ‹•ƒ –‹˜ƒ–‡†–Š”‘—‰Š’Š‘•’Š‘”›Žƒ–‹‘„›—’‘ •–‹—Žƒ–‹‘™‹–Š‰ ‹ ʹͻͷ ‡ŽŽ•ͺͷǤ

‘–Š‡”‰‡‡–Šƒ–Šƒ•”‡ ‡–Ž›„‡‡•—‰‰‡•–‡†–‘’Žƒ›ƒ”‘Ž‡‹–Š‡”‡‰—Žƒ–‹‘‘ˆ CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡•‡ ”‡–‹‘‹•–Š‡’—–ƒ–‹˜‡–—‘”•—’’”‡••‘”‰‡‡ dachshund homolog 1ȋDACH1ȌǤ‹Ž‡ ‹‰‘ˆDACH1‹ ʹͻͷ ‡ŽŽ•‹ ”‡ƒ•‡†CYP11B2 ‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘™Š‹Ž‡‘˜‡”‡š’”‡••‹‘‘ˆDACH1 †‡ ”‡ƒ•‡†ƒŽǦ †‘•–‡”‘‡’”‘†— –‹‘ͺ͸Ǥ—–ƒ–‹‘‹–Š‹•‰‡‡Šƒ•„‡‡‹†‡–‹ˆ‹‡†‹–™‘’ƒ–‹‡–• ™‹–Š’”‹ƒ”›ƒŽ†‘•–‡”‘‹•ƒ†–Š‡‹”ˆƒ‹Ž›‡„‡”•ǡ™Š‘•‡ ƒ•‡•™‹ŽŽ„‡†‹• —••‡† ‹–Š‹•™‘”Ǥ

6.2 Classes of ion channels of major interest for this work ‘ Šƒ‡Ž•’Žƒ›ƒ‹’‘”–ƒ–”‘Ž‡‹‹‘–”ƒ•’‘”–ƒ ”‘•• ‡ŽŽ‡„”ƒ‡•ƒ†–Š‡‹” ˆ— –‹‘Š‡ƒ˜‹Ž›‹ˆŽ—‡ ‡• ‡ŽŽ—Žƒ”‹‘Š‘‡‘•–ƒ•‹•ǡ‹Ǥ‡Ǥ–Š‡ƒ‹–‡ƒ ‡‘ˆƒ‹‘ǯ• ‘ ‡–”ƒ–‹‘‰”ƒ†‹‡–™‹–Š‹–Š‡ ‡ŽŽƒ†‹–••—””‘—†‹‰•ͺ͹ǡͺͺǤŠ‹•„ƒŽƒ ‡‹•–Š‡„ƒǦ •‹•ˆ‘”–Š‡‡„”ƒ‡”‡•–‹‰’‘–‡–‹ƒŽ‘ˆ‡ƒ Š ‡ŽŽͺ͹Ǥ ‘ Šƒ‡Žƒ –‹˜‹–›‹• Ž‘•‡Ž› Ž‹‡†–‘–Š‡ƒ –‹˜ƒ–‹‘‘ˆ•‹‰ƒŽ‹‰ ƒ• ƒ†‡•™‹–Š‹–Š‡ ‡ŽŽǡ‡‹–Š‡”–Š”‘—‰Šƒ†ƒ’–‡” ‘Ž‡ —Ž‡•‘”†‹”‡ –Ž›„›‹ ”‡ƒ•‹‰‹–”ƒ ‡ŽŽ—Žƒ” ‘ ‡–”ƒ–‹‘•‘ˆ–Š‡‡••‡‰‡”‹‘ ƒʹΪ”‡ˆͺ͹ǡͺͺǤ‘•‡“—‡–Ž›ǡ‹‘ Šƒ‡Žƒ –‹˜‹–›‹• ”— ‹ƒŽ‹ ‡ŽŽ—Žƒ”ˆ— –‹‘Ǥ

 Ύ ǣ‡”˜‡‰”‘™–Šˆƒ –‘” Ǣͳǣ— Ž‡ƒ””‡ ‡’–‘”Ǧ”‡Žƒ–‡†’”‘–‡‹ͳǢǦͳǣ‡”˜‡‰”‘™–Š ˆƒ –‘” ”‡•’‘•‡‡Ž‡‡–ͳǢ†ǦͶǡͷǣƒ†”‡ƒŽͶǡͷ ͳ͸ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ Š‹•™‘” ‘’”‹•‡•ˆ— –‹‘ƒŽƒ†’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ•–—†‹‡•‘ˆ‹‘ Šƒ‡Ž•‹˜‘Ž˜‡† ‹ „Ž‘‘† ’”‡••—”‡ ”‡‰—Žƒ–‹‘ ƒ† †›•”‡‰—Žƒ–‹‘Ǥ Š‡•‡ Šƒ‡Ž•ǡ‹Ǥ‡Ǥ

‹”͵ǤͶȀ ͶȀ ͷƒ†ƒ˜͵ǤʹȀͳ ǡ„‡Ž‘‰–‘–Š‡ Žƒ••‡•‘ˆ ’”‘–‡‹Ǧ ‘—’Ž‡† ‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž•ƒ†˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•Ǥ„”‹‡ˆ‹Ǧ –”‘†— –‹‘‹–‘–Š‡•‡ Žƒ••‡•‘ˆ‹‘ Šƒ‡Ž•ƒ•™‡ŽŽƒ•–Š‡‹”ƒ••—‡†ˆ— –‹‘•‹–Š‡ ‘”ƒŽƒ†”‡ƒŽ‰Žƒ†™‹ŽŽ„‡’”‡•‡–‡†‹–Š‡ˆ‘ŽŽ‘™‹‰•‡ –‹‘•Ǥ



&ŝŐƵƌĞϮ͘^ƚĞƉƐŽĨĂůĚŽƐƚĞƌŽŶĞƐLJŶƚŚĞƐŝƐŝŶƚŚĞ'ĐĞůů͕ĞŶnjLJŵĞƐŝŶǀŽůǀĞĚĂŶĚƐƵďĐĞůůƵůĂƌůŽĐĂůŝnjĂƚŝŽŶ͘^ƚZ ƚƌĂŶƐƉŽƌƚƐĐŚŽůĞƐƚĞƌŽůĨƌŽŵƚŚĞŽƵƚĞƌŵŝƚŽĐŚŽŶĚƌŝĂůŵĞŵďƌĂŶĞ;KDDͿƚŽƚŚĞŝŶŶĞƌŵŝƚŽĐŚŽŶĚƌŝĂůŵĞŵͲ ďƌĂŶĞ;/DDͿ͘ŚŽůĞƐƚĞƌŽůƐŝĚĞĐŚĂŝŶĐůĞĂǀĂŐĞďLJWϰϱϬƐĐĐͬzWϭϭϭƌĞƐƵůƚƐŝŶĨŽƌŵĂƚŝŽŶŽĨƉƌĞŐŶĞŶŽůŽŶĞ͘ ϯƘͲ,^ĂŶĚWϰϱϬĐϮϭͬzWϮϭĂƌĞůŽĐĂůŝnjĞĚŝŶƚŚĞZ͘ůĚŽƐƚĞƌŽŶĞƐLJŶƚŚĂƐĞ;WϰϱϬĂůĚŽͬzWϭϭϮͿĐĂƚĂůLJnjĞƐ ƚŚĞůĂƐƚƚǁŽƐƚĞƉƐŽĨĂůĚŽƐƚĞƌŽŶĞƐLJŶƚŚĞƐŝƐŝŶƚŚĞŵŝƚŽĐŚŽŶĚƌŝĂ͘ĚĂƉƚĞĚĨƌŽŵ'ĂůůŽͲWĂLJĞƚ͕ϮϬϭϲƵŶĚĞƌĐŽŶͲ ƐŝĚĞƌĂƚŝŽŶŽĨWĂLJŶĞĂŶĚ,ĂůĞƐ͕ϮϬϬϰϮϮ͕ϴϵ͘ 

ͳ͹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ

6.2.1 Voltage-gated calcium channels –”ƒ ‡ŽŽ—Žƒ”ƒʹΪ•‡”˜‡•ƒ•ƒ‹’‘”–ƒ–—„‹“—‹–‘—••‡ ‘†‡••‡‰‡”Ǥ –‹•’Žƒ›•ƒ ”— ‹ƒŽ”‘Ž‡‹ƒ˜ƒ”‹‡–›‘ˆ‡ Šƒ‹•••— Šƒ•‡—”‘–”ƒ•‹––‡””‡Ž‡ƒ•‡ǡ—• Ž‡ ‘Ǧ –”ƒ –‹‘ƒ•™‡ŽŽƒ• ‡ŽŽ—Žƒ”†‹ˆˆ‡”‡–‹ƒ–‹‘ƒ†’”‘Ž‹ˆ‡”ƒ–‹‘ͻͲǤƒŽ ‹—Ǧ†‡’‡†‡–•‹‰Ǧ ƒŽ‹‰ ƒ• ƒ†‡•ƒ”‡–”‹‰‰‡”‡†—’‘ƒ‹ ”‡ƒ•‡‘ˆ‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•ǤŠ‹• ƒ ‡‹–Š‡”‘ —”–Š”‘—‰ŠƒʹΪ”‡Ž‡ƒ•‡ˆ”‘‹–”ƒ ‡ŽŽ—Žƒ”•–‘”‡•‹–Š‡‘”–Š”‘—‰Š‹ˆŽ—š ˆ”‘–Š‡‡š–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡ͻͲǤ

‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž• ƒ‹ ”‡ƒ•‡‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•–Š”‘—‰Š–Š‡Žƒ––‡” ‡ Šƒ‹•ͻͲǤŠ‡‹”ƒ„‹Ž‹–›–‘ ‘†— –‹‘•‹•†‡’‡†‡–‘‡„”ƒ‡’‘–‡–‹ƒŽǡ‘’‡Ǧ ‹‰ƒ–†‡’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•ͻͳǤŠ‡›‡š‹•–‹͵•–ƒ‰‡•ǣ Ž‘•‡†ǡƒ –‹˜ƒ–‡†ƒ†‹ƒ –‹˜ƒ–‡†Ǥ  –‹˜ƒ–‹‘”‡ˆ‡”•–‘–Š‡‘’‡‹‰‘ˆ–Š‡ Šƒ‡Žƒ•ƒ”‡•—Ž–‘ˆ‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ǡ ™Š‹Ž‡‹ƒ –‹˜ƒ–‹‘†‡• ”‹„‡•ƒ•–ƒ–‡ˆ”‘™Š‹ Š–Š‡‘’‡•–ƒ–‡ ƒ‘–„‡‹‡†‹ƒ–‡Ž› ”‡ƒ Š‡†„—–”‡“—‹”‡•ƒ”‡ƒ –‹˜ƒ–‹‘’‡”‹‘†Ǥ‹‡ƒ –‹˜ƒ–‹‘ǡ‹–‹•ƒŽ•‘„”‘—‰Š–‘„›†‡Ǧ ’‘Žƒ”‹œƒ–‹‘ʹ͵Ǥ‡ƒ –‹˜ƒ–‹‘‹•–Š‡’”‘ ‡••‘ˆ Šƒ‡Ž Ž‘•‹‰‹”‡•’‘•‡–‘”‡’‘Žƒ”‹œƒǦ –‹‘‘ˆ–Š‡‡„”ƒ‡ͻʹǤ

‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•‰‡‡”ƒŽŽ›ˆ‘”Š‡–‡”‘—Ž–‹‡”•ǡ ‘•‹•–‹‰‘ˆ†‹ˆˆ‡”Ǧ

‡–•—„—‹–•ǣȽͳǡȽʹɁǡȾǡƒ†ɀͻͳȋ ‹‰—”‡͵ȌǤŠƒ‡Ž ‘’‘•‹–‹‘ ƒ˜ƒ”›ƒ‘‰†‹ˆǦ

ˆ‡”‡– –›’‡• ‘ˆ ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ͻ͵ǡͻͶǤ Š‹Ž‡ –Š‡ Ƚͳ •—„—‹–• ˆ‘” –Š‡ Šƒ‡Žǯ•’‘”‡ǡ‘–Š‡”•—„—‹–•ƒ›ƒˆˆ‡ –‰ƒ–‹‰ƒ† Šƒ‡Ž‡š’”‡••‹‘Ž‡˜‡Ž•ͻ͵Ǥ ‹˜‡

†‹ˆˆ‡”‡– Žƒ••‡•‘ˆȽͳ•—„—‹–• ƒ„‡†‹•–‹‰—‹•Š‡††‡’‡†‹‰‘–Š‡–›’‡‘ˆ —””‡– –Š‡›‰‡‡”ƒ–‡ǣǦ–›’‡ǡǦ–›’‡ǡȀǦ–›’‡ǡǦ–›’‡ƒ†Ǧ–›’‡ȋ ‹‰—”‡͵ȌǤŠ‹Ž‡ǡǡȀ ƒ†  Šƒ‡Ž• ƒ”‡ Š‹‰Š ˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡†ǡ Ǧ–›’‡ Šƒ‡Ž• ƒ”‡ Ž‘™ ˜‘Ž–ƒ‰‡Ǧƒ –‹Ǧ ˜ƒ–‡†ͻͳǡͻͷǤ –•Š‘—Ž†„‡‘–‡†–Šƒ–‹ ‘–”ƒ•––‘–Š‡Š‡–‡”‘—Ž–‹‡”‹ Š‹‰Š˜‘Ž–ƒ‰‡Ǧƒ Ǧ

–‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǡ–Š‡Ƚͳ•—„—‹–•‘ˆŽ‘™˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ƒ’Ǧ ’‡ƒ”–‘„‡ƒ„Ž‡–‘ˆ‘”ˆ—ŽŽ›ˆ— –‹‘ƒŽ ƒŽ ‹— Šƒ‡Ž•‘–Š‡‹”‘™ǡ™Š‹ Š Ž‘•‡Ž› ‹””‘” –Š‡ ‰ƒ–‹‰ „‡Šƒ˜‹‘” ‘ˆ ƒ–‹˜‡ Ǧ–›’‡ Šƒ‡Ž• ™‹–Š‘—– ”‡“—‹”‹‰ ƒ••‘ ‹ƒ–‹‘ ™‹–Šƒ—š‹Ž‹ƒ”›•—„—‹–•ͻ͸ǡͻ͹Ǥ

–”— –—”ƒŽŽ›ǡȽͳ•—„—‹–• ‘•‹•–‘ˆͶŠ‘‘Ž‘‰‘—•”‡’‡ƒ–•ȋ Ǧ Ȍǡ‡ƒ Š ‘•‹•–‹‰‘ˆ•‹š –”ƒ•‡„”ƒ‡•‡‰‡–•ȋͳǦ͸ȌͻͳǤŠ‹Ž‡ͷƒ†͸Ž‹‡–Š‡’‘”‡ǡ–Š‡‘–Š‡”–”ƒ•Ǧ ‡„”ƒ‡•‡‰‡–•ƒ”‡‹˜‘Ž˜‡†‹‰ƒ–‹‰ƒ†˜‘Ž–ƒ‰‡•‡•‹‰ǤͶ ‹• ’‘•‹–‹˜‡Ž› Šƒ”‰‡††—‡–‘ƒ’ƒ––‡”‘ˆ„ƒ•‹ ƒ”‰‹‹‡‘”Ž›•‹‡”‡•‹†—‡•ƒŽ–‡”‹‰™‹–Š— Šƒ”‰‡† ”‡•‹†—‡•ȋ ‹‰—”‡͵ȌǤŠƒ‰‡•‹–Š‡‡Ž‡ –”‹ ˆ‹‡Ž† ƒ—•‡–Š‡•‡‰‡––‘‘˜‡ǡƒ‡ ŠǦ ƒ‹•‡ƒ„Ž‹‰‹–•ˆ— –‹‘ƒ•ƒ˜‘Ž–ƒ‰‡•‡•‘”ʹ͵ǡͻͳǡͻͺǤŠ‡’‘”‡Ž‘‘’„‡–™‡‡ͷƒ†͸

ͳͺ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‘–”‘Ž• Šƒ‡Ž ‘†— –ƒ ‡ƒ†•‡Ž‡ –‹˜‹–›ǤƒŽ ‹—•‡Ž‡ –‹˜‹–›‹•‡†‹ƒ–‡†„›‰Ž—–ƒǦ ƒ–‡”‡•‹†—‡•‹–Š‹•”‡‰‹‘ʹ͵ǡͻͻǤ

Ǧ–›’‡ Šƒ‡Ž••‡•‹–‹˜‡–‘–Š‡ ‘’‘—† Žƒ••‘ˆ†‹Š›†”‘’›”‹†‹‡•™‡”‡ˆ‹”•–’—”‹Ǧ ˆ‹‡†ˆ”‘•‡Ž‡–ƒŽ—• Ž‡ͻͷǡͳͲͲǤ ƒ††‹–‹‘ǡ–Š‡› ƒ„‡ˆ‘—†‹ƒŽƒ”‰‡˜ƒ”‹‡–›‘ˆ ‡ŽŽ•ǡ ‹ Ž—†‹‰ ƒ”†‹ƒ  ›‘ ›–‡•ǡ ‡—”‘• ƒ† ‡†‘ ”‹‡ ‡ŽŽ•ǡ ™Š‡”‡ –Š‡› ˆƒ ‹Ž‹–ƒ–‡ Š‘”Ǧ ‘‡”‡Ž‡ƒ•‡ͻ͵ǡͳͲͳȂͳͲ͵Ǥ‡—”‘•ƒ”‡ƒŽ•‘ƒ‹’‘”–ƒ–•‹–‡‘ˆƒ –‹‘ˆ‘”Ǧ–›’‡ ŠƒǦ ‡Ž•ͻʹǡͳͲͶǤǦ–›’‡ǡǦ–›’‡ƒ†Ǧ–›’‡ Šƒ‡Ž•ƒ”‡’”‡•‡–‹‡—”‘ƒŽ ‡ŽŽ•‘ˆ–Š‡ ‡”‡Ǧ „‡ŽŽ—ͳͲͷǡͳͲ͸ǤǦ–›’‡ Šƒ‡Ž•™‡”‡ˆ‹”•–‹†‡–‹ˆ‹‡†‹‰—‹‡ƒ’‹‰‡—”‘•ͻ͵ǡͳͲ͹ǤŠ‡›ƒ”‡ ƒŽ•‘‡š’”‡••‡†‹ ƒ”†‹ƒ ƒ†•‘‘–Š—• Ž‡›‘ ›–‡•ͻͳǡͳͲͺǡͳͲͻǤ

‘–ŠǦ–›’‡ƒ†Ǧ–›’‡ —””‡–•Šƒ˜‡„‡‡†‡–‡ –‡†‹–Š‡ƒ†”‡ƒŽ ‘ˆ†‹ˆˆ‡”‡–•’‡Ǧ ‹‡•Ǥ —”–Š‡”‘”‡ǡǦ–›’‡ —””‡–•Šƒ˜‡„‡‡”‡ ‘”†‡†‹”ƒ–  ‡ŽŽ•ƒ†‡š’”‡••‹‘

‘ˆ–Š‡Ǧ–›’‡ Šƒ‡Žƒ˜ʹǤʹ™ƒ•†‡–‡ –‡†‹–Š‡‘”ƒŽŠ—ƒ ʹ͵ǡͳͳͲȂͳͳͶǤ



&ŝŐƵƌĞϯ͘sŽůƚĂŐĞͲŐĂƚĞĚĐĂůĐŝƵŵĐŚĂŶŶĞůƐ͘ͿdŚĞɲϭƐƵďƵŶŝƚĐŽŶƐŝƐƚƐŽĨϰŚŽŵŽůŽŐŽƵƐƌĞƉĞĂƚƐ;/Ͳ/sͿ͕ĞĂĐŚ ĐŽŵƉƌŝƐŝŶŐϲƚƌĂŶƐŵĞŵďƌĂŶĞƐĞŐŵĞŶƚƐ;^ϭͲ^ϲͿ͘^ϱĂŶĚ^ϲůŝŶĞƚŚĞƉŽƌĞ͘^ϰĨŽƌŵƐƚŚĞǀŽůƚĂŐĞƐĞŶƐŽƌ͘/ƚŝƐ ƉŽƐŝƚŝǀĞůLJĐŚĂƌŐĞĚĚƵĞƚŽĂŶĂůƚĞƌŝŶŐƉĂƚƚĞƌŶŽĨďĂƐŝĐĂŶĚƵŶĐŚĂƌŐĞĚƌĞƐŝĚƵĞƐϮϯ͕ϵϭ͘ĞƉŝĐƚŝŽŶĂĚĂƉƚĞĚĨƌŽŵ ĂƚƚĞƌĂůů͕ϮϬϭϭĂŶĚĂŶŝŝůĞƚĂů͕͘ϮϬϭϲϵϲ͕ϭϭϱ͘Ϳ^ƵďƵŶŝƚĐŽŵƉŽƐŝƚŝŽŶŽĨĂŚŝŐŚǀŽůƚĂŐĞͲĂĐƚŝǀĂƚĞĚĂϮнĐŚĂŶŶĞů͘ ĚĂƉƚĞĚĨƌŽŵĂƚƚĞƌĂůů͕ϮϬϬϬĂŶĚƵƌĂĞŝĂŶĚzĂŶŐ͕ϮϬϭϬϵϯ͕ϭϭϲͿKǀĞƌǀŝĞǁŽĨƚŚĞĚŝĨĨĞƌĞŶƚǀŽůƚĂŐĞͲŐĂƚĞĚĂϮн ϵϯ ĐŚĂŶŶĞůƐ͕ƚŚĞŝƌĐŽƌƌĞƐƉŽŶĚŝŶŐɲϭƐƵďƵŶŝƚƐĂŶĚŐĞŶĞƐ ͘

ͳͻ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ 6.2.1.1 L-type and T-type channels and their role in aldosterone production Ǧ–›’‡ Šƒ‡Ž• ƒ –‹˜ƒ–‡ ƒ– ‘”‡ Š›’‡”’‘Žƒ”‹œ‡† ‡„”ƒ‡ ’‘–‡–‹ƒŽ• –Šƒ Ǧ–›’‡ Šƒ‡Ž•ȋ’‘•‹–‹˜‡–‘Ǧ͹Ͳ˜‡”•—•’‘•‹–‹˜‡–‘ǦͳͲǡ”‡•’‡ –‹˜‡Ž›ȌǤ —”–Š‡”‘”‡ǡǦ –›’‡ Šƒ‡Ž•‹ƒ –‹˜ƒ–‡ˆƒ•–‡”ǡ„—–†‡ƒ –‹˜ƒ–‡ƒ†”‡ƒ –‹˜ƒ–‡‘”‡•Ž‘™Ž›–ŠƒǦ–›’‡ Šƒ‡Ž•ʹ͵ǡͻʹǤ

Ǧ–›’‡ Šƒ‡Ž•ƒ”‡ˆ‘”‡†„›–Š‡Ƚ•—„—‹–•Ƚͳ ǡȽͳ ƒ†Ƚͳ ǡƒŽ•‘”‡ˆ‡””‡†–‘ƒ•ƒ˜͵Ǥͳǡ

͵Ǥʹǡ͵Ǥ͵ǡ”‡•’‡ –‹˜‡Ž›ͻ͵ȋ ‹‰—”‡͵ȌǤ –Š‡”ƒ–ƒ†„‘˜‹‡ ǡȽͳ ‹•Š‹‰ŠŽ›‡š’”‡••‡†ǡ

™Š‹Ž‡‘Ž›Ž‘™‡š’”‡••‹‘Ž‡˜‡Ž•‘ˆȽͳ  ƒ„‡†‡–‡ –‡†ƒ†Ƚͳ ƒ’’‡ƒ”•–‘Žƒ ‡š’”‡•Ǧ

•‹‘ ‘’Ž‡–‡Ž›ʹ͵ǡͳͳ͹ǤȽͳ ǡ‡ ‘†‡†„›–Š‡‰‡‡CACNA1Hǡ‹•ƒŽ•‘‡š’”‡••‡†‹–Š‡‘”Ǧ ƒŽŠ—ƒƒ†”‡ƒŽ ǡƒ•™‡ŽŽƒ•‹–Š‡ƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ʹͻͷͳͳͲǡͳͳͺǡͳͳͻǤ 

–Š‹• ‡ŽŽŽ‹‡ǡ‡š’‘•—”‡–‘ƒŽ†‘•–‡”‘‡‹†— ‡•Ƚͳ ‡š’”‡••‹‘ƒ•™‡ŽŽƒ•Ǧ–›’‡ —”Ǧ ”‡–ͳͳͻǤ

Ǧ–›’‡ Šƒ‡Ž• ƒ ‘•‹•–‘ˆ–Š‡Ƚ•—„—‹–•ȽͳǡȽͳǡȽͳƒ†Ƚͳ ȋƒ˜ͳǤͳǡͳǤʹǡͳǤ͵ǡͳǤͶ

”‡•’‡ –‹˜‡Ž›ǡ ‘’ƒ”‡ ‹‰—”‡͵ȌͻͳǤ –Š‡”ƒ– ƒ† ʹͻͷ ‡ŽŽ•ǡ„‘–ŠȽͳƒ†Ƚͳƒ”‡

‡š’”‡••‡†ǡ™‹–ŠȽͳ„‡‹‰–Š‡‘•–ƒ„—†ƒ–ʹ͵ǡͳͳͻǡͳʹͲǤȽͳƒ†Ƚͳ‡š’”‡••‹‘Šƒ•ƒŽ•‘

„‡‡ ‘ˆ‹”‡†‹–Š‡‘”ƒŽŠ—ƒ ͳͳͲǡͳʹͳǤŠ‡Ƚͳ•—„—‹–‹•‡ ‘†‡†„›–Š‡‰‡‡

CACNA1DͻͳǤ ”‘Š‡”‡‘ǡ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ƒ†–Š‡‹”Ƚͳ•—„—‹–•™‹ŽŽ„‡

”‡ˆ‡””‡†–‘„›–Š‡‰‡‡ƒ‡‘ˆ–Š‡ ‘””‡•’‘†‹‰Ƚͳ•—„—‹–Ǧ‡Ǥ‰Ǥƒ˜ͳǤ͵ƒ†Ƚͳ™‹ŽŽ „‡ ƒŽŽ‡†ͳǤ

‘–ŠǦ–›’‡ƒ†Ǧ–›’‡ Šƒ‡Ž•ƒ‹ˆ‡•–†‹ˆˆ‡”‡–‹ƒŽ’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡•ǣǦ –›’‡ Šƒ‡Ž•ƒ”‡‘”‡•‡•‹–‹˜‡–ŠƒǦ–›’‡ Šƒ‡Ž•–‘„Ž‘ ‹‰„›†ʹΪǡ†‹Š›†”‘Ǧ ’›”‹†‹‡•Ž‹‡‹ˆ‹†‡’‹‡ǡƒ•™‡ŽŽƒ•’Š‡›ŽƒŽ›Žƒ‹‡•Ž‹‡˜‡”ƒ’ƒ‹ŽͳͲͶǡͳʹʹǡͳʹ͵ǤŠ‡‹” —””‡–• ƒ„‡‡Šƒ ‡†„›ƒ›ͺ͸ͶͶͳʹͶǤ‡Žƒ–‹˜‡Ž›•‡Ž‡ –‹˜‡‹Š‹„‹–‹‘‘ˆǦ–›’‡ Šƒ‡Ž• ‘˜‡” Ǧ–›’‡ Šƒ‡Ž• ƒ „‡ ƒ Š‹‡˜‡† ™‹–Š ‹ʹΪǡ ƒ‹Ž‘”‹†‡ ƒ† ‹„‡Ǧ ˆ”ƒ†‹ŽͳͲͶǡͳʹͷȂͳʹ͹ǤŠ‡Žƒ––‡”‹•ƒ’Šƒ”ƒ ‡—–‹ ƒŽ–Šƒ–™ƒ•‹–”‘†— ‡†ˆ‘”–Š‡–”‡ƒ–‡–‘ˆ Š›’‡”–‡•‹‘ƒ†ƒ‰‹ƒ’‡ –‘”‹•ǤŠ‘”–Ž›ƒˆ–‡”‹–•ƒ’’”‘˜ƒŽ„›–Š‡ ǡ‹–™ƒ•™‹–ŠǦ †”ƒ™ˆ”‘–Š‡ƒ”‡–†—‡–‘’‘••‹„Ž‡•‡˜‡”‡†”—‰‹–‡”ƒ –‹‘•ͳʹͺȂͳ͵ͲǤ

–Š‡  ‡ŽŽǡ„‘–ŠǦ–›’‡ƒ†Ǧ–›’‡ Šƒ‡Ž•ƒ’’‡ƒ”–‘„‡‹˜‘Ž˜‡†‹’”‘†— –‹‘‘ˆ ƒŽ†‘•–‡”‘‡ȋ ‘’ƒ”‡‡Ǥ‰Ǥʹ͵ȌǤ  ”‡ƒ•‡†‡š–”ƒ ‡ŽŽ—Žƒ”Ϊ ‘ ‡–”ƒ–‹‘•ƒ –‹˜ƒ–‡˜‘Ž–Ǧ ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•–Š”‘—‰Š‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ʹ͵ǡͳ͵ͳǤ–Ž‘™‡”Ϊ ‘Ǧ ‡–”ƒ–‹‘•ǡ–Š‡‡ˆˆ‡ –ƒ’’‡ƒ”•–‘„‡‘•–Ž›†‡’‡†‡–‘Ǧ–›’‡ Šƒ‡Ž•Ǥ–‹ ”‡ƒ•Ǧ ‹‰’Š›•‹‘Ž‘‰‹ ƒŽ ‘ ‡–”ƒ–‹‘ǡǦ–›’‡ Šƒ‡Ž•ǡ”‡“—‹”‹‰•–”‘‰‡”‡„”ƒ‡†‡’‘Ǧ Žƒ”‹œƒ–‹‘ˆ‘”ƒ –‹˜ƒ–‹‘ǡƒ”‡‹˜‘Ž˜‡†‹–Š‡’”‘ ‡••ƒ•™‡ŽŽǤ– ‘ ‡–”ƒ–‹‘•ƒ„‘˜‡

ʹͲ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ –Š‡’Š›•‹‘Ž‘‰‹ ƒŽ”ƒ‰‡ǡ–Š‡•‹‰ƒŽ‹•ƒ‹Ž›†‡’‡†‡–‘Ǧ–›’‡ Šƒ‡Ž•ʹ͵ǡͳʹ͸ǡͳ͵ͳǡͳ͵ʹǤ  ”‡ƒ•‡†•‡•‹–‹˜‹–›‘ˆǦ–›’‡ Šƒ‡Ž•–‘ΪǦ‡†‹ƒ–‡††‡’‘Žƒ”‹œƒ–‹‘ ƒ—•‡†„›Š›Ǧ ’‘‘•‘•‹•ǡƒ†–Š—•‹ ”‡ƒ•‡† ‡ŽŽ˜‘Ž—‡ǡƒ•™‡ŽŽƒ•ƒƒʹΪǦ†‡’‡†‡–•Š‹ˆ–‘ˆǦ–›’‡ Šƒ‡Ž•–‘„‡ƒ –‹˜ƒ–‡†ƒ–‘”‡Š›’‡”’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•‹†— ‡† „› ƒ  Šƒ• „‡‡•—‰‰‡•–‡†‹•‘‡ ‡ŽŽ‘†‡Ž•ʹ͵ǡͳ͵͵Ȃͳ͵͸Ǥ

‰ Ǧ•–‹—Žƒ–‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Šƒ•„‡‡•—‰‰‡•–‡†–‘‘•–Ž›‹˜‘Ž˜‡Ǧ–›’‡ Šƒ‡Ž•ǡ™Š‹Ž‡Ǧ–›’‡ Šƒ‡Žƒ –‹˜‹–›ƒ’’‡ƒ”•–‘„‡‹Š‹„‹–‡†ǡƒ‡ˆˆ‡ –’‘••‹„Ž›‹Ǧ ˜‘Ž˜‹‰•‹—Ž–ƒ‡‘—• ’”‘–‡‹Ǧ‡†‹ƒ–‡†ƒ –‹˜ƒ–‹‘‘ˆǦ–›’‡ Šƒ‡Ž•ƒ†‹ƒ –‹˜ƒǦ –‹‘‘ˆǦ–›’‡ Šƒ‡Ž•ʹ͵ǡ͵Ͷǡͳ͵ͳǡͳ͵͹ǡͳ͵ͺǡ  ‘ ‡”–™‹–Š–Š‡•‡‘„•‡”˜ƒ–‹‘•ǡǦ–›’‡ Šƒ‡Ž ‹Š‹„‹–‹‘„›‹„‡ˆ”ƒ†‹Žƒ†–‡–”ƒ†”‹‡”‡†— ‡‰ Ǧ•–‹—Žƒ–‡†ƒʹΪ‹ˆŽ—šƒ†ƒŽ†‘•Ǧ –‡”‘‡ ’”‘†— –‹‘ͳʹ͸ǡͳ͵ͻǤ ‘™‡˜‡”ǡ •‘‡ •–—†‹‡• •—’’‘”– ƒ ‹˜‘Ž˜‡‡– ‘ˆ Ǧ–›’‡ Šƒ‡Ž•Ǥ ‘” ‹•–ƒ ‡ǡ ‰  ƒ† Ϊ •–‹—Žƒ–‡† ’”‘†— –‹‘ ‘ˆ ƒŽ†‘•–‡”‘‡ ƒ „‡ „Ž‘ ‡†„›Ǧ–›’‡ Šƒ‡Ž„Ž‘ ‡”‹ˆ‡†‹’‹‡‹ ʹͻͷ ‡ŽŽ•ͳͶͲǤ‡˜‡”–Š‡Ž‡••ǡ–Š‡”‘Ž‡ ‘ˆǦ–›’‡ Šƒ‡Ž•‹‰Š–„‡‹‘”Ǥ –Š‡‹”•–—†‹‡•‘ˆ–Š‡†—ƒŽǦ–›’‡ȀǦ–›’‡ Šƒ‡Ž ‹Š‹„‹–‘”‡ˆ‘‹†‹’‹‡ǡ ƒ‰ƒ™ƒet al.”‡’‘”––Šƒ–‹„‡ˆ”ƒ†‹Ž™ƒ•ƒ„Ž‡–‘”‡†— ‡‰ Ǧ ‹†— ‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ʹͻͷ ‡ŽŽ•‘”‡’‘–‡–Ž›–Šƒ‹ˆ‡†‹’‹‡Ǥ‹ˆ‡†‹Ǧ ’‹‡ǡŠ‘™‡˜‡”ǡ™ƒ•ƒ‘”‡’‘–‡–‹Š‹„‹–‘”‘ˆΪǦ‡†‹ƒ–‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Ǥ ‹„‡ˆ”ƒ†‹Ž”‡†— ‡†„‘–Š‰ ƒ†ΪǦ•–‹—Žƒ–‡†CYP11B2‡š’”‡••‹‘ǡ™Š‹Ž‡‹ˆ‡†‹’‹‡ ‘Ž›†‹‹‹•Š‡†ΪǦ‡†‹ƒ–‡†‡ˆˆ‡ –•Ǥˆ‘‹†‹’‹‡™ƒ•–Š‡‘•–’‘–‡–‹Š‹„‹–‘”™‹–Š „‘–Š•–‹—Ž‹ͳͶͳǤŠ‡•‡”‡•—Ž–••—‰‰‡•–ƒ‘”‡’”‘‘— ‡†‹ˆŽ—‡ ‡‘ˆǦ–›’‡ Šƒ‡Ž• ‘‰ Ǧ‡†‹ƒ–‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǡ™‹–Š‘—–ˆ—ŽŽ›†‹•‹••‹‰ƒ’—–ƒ–‹˜‡ˆ— Ǧ –‹‘‘ˆǦ–›’‡ Šƒ‡Ž•Ǥˆ‘–‡ǡ‹–Šƒ•„‡‡•—‰‰‡•–‡†–Šƒ–Ǧ–›’‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹—

Šƒ‡Ž•‘†—Žƒ–‡ ͵Ǧ†‡’‡†‡–ƒʹΪ”‡Ž‡ƒ•‡˜‹ƒ‹–‡”ƒ –‹‘™‹–Š ͵ʹ͵Ǥ

–Š‹•™‘”ǡ–Š‡‡ˆˆ‡ –•‘ˆ—–ƒ–‹‘•‹–Š‡Ǧ–›’‡ Šƒ‡Žͳ ‘ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘™‹ŽŽ„‡‹˜‡•–‹‰ƒ–‡†Ǥˆˆ‡ –•‘ˆΪƒ†‰ •–‹—Žƒ–‹‘ƒ•™‡ŽŽƒ•‹Š‹„‹–‹‘ „›‹„‡ˆ”ƒ†‹Ž™‹ŽŽ’Žƒ›ƒ”‘Ž‡‹•‘‡‡š’‡”‹‡–•Ǥ

Ǧƒ†Ǧ–›’‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•Šƒ˜‡„‡‡‹’Ž‹ ƒ–‡†‹ƒ˜ƒ”‹‡–›‘ˆ†‹•Ǧ ‡ƒ•‡•ǣ ‘”‹•–ƒ ‡ǡŽ‘••‘ˆˆ— –‹‘‹ͳŠƒ•„‡‡ƒ••‘ ‹ƒ–‡†™‹–Š†‡ƒˆ‡••ƒ† „”ƒ Š› ƒ”†‹ƒͳͶʹȂͳͶͶǤ‘–Š—–ƒ–‹‘•‹CACNA1Dƒ†CACNA1H‹‰Š–’Žƒ›ƒ”‘Ž‡‹ƒ—Ǧ –‹••’‡ –”—†‹•‘”†‡”•ƒ†‡’‹Ž‡’•›ͳͶͷȂͳͶͻǤ —”–Š‡”‘”‡ǡ•–—†‹‡•‹CACNA1H‘ Ǧ ‘—–ƒ†‘ Ǧ†‘™‹ ‡•—‰‰‡•––Šƒ–‹–’Žƒ›•ƒ”‘Ž‡‹‹–”‹ ‘š‹†‡ȋȌǦ‡†‹ƒ–‡† •‘‘–Š—• Ž‡”‡Žƒšƒ–‹‘‹–Š‡Š‡ƒ”–ƒ•™‡ŽŽƒ•‹–Š‡’‡” ‡’–‹‘‘ˆ’ƒ‹ͳͷͲȂͳͷʹǤŠ‡ Žƒ––‡”‡ˆˆ‡ –‹• ‘””‘„‘”ƒ–‡†„›•–—†‹‡•—•‹‰–Š‡‹Š‹„‹–‘”‹„‡ˆ”ƒ†‹Žͳͷ͵ǡͳͷͶǤ

ʹͳ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ †‡–ƒ‹Ž‡††‡• ”‹’–‹‘‘ˆCACNA1Hƒ†CACNA1D—–ƒ–‹‘•‹’”‹ƒ”›ƒŽ†‘•–‡”‘‹• ™‹ŽŽ„‡‰‹˜‡‹•‡ –‹‘•͸Ǥ͵ǤʹǤͳǤʹǡ͸Ǥ͵ǤʹǤʹǤͶƒ†͸Ǥ͵ǤʹǤʹǤͷǤ

6.2.2 G protein-coupled inwardly-rectifying potassium channels Ϊ‹•–Š‡‘•–ƒ„—†ƒ– ƒ–‹‘‹–Š‡‹–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡ǡ™Š‹Ž‡ƒΪ‹•–Š‡Š‹‰Š‡•– ‘Ǧ ‡–”ƒ–‡†‘‡‹–Š‡‡š–”ƒ ‡ŽŽ—Žƒ”•’ƒ ‡ͳͷͷǤŠ‹•‰”ƒ†‹‡–‹•ƒ‹–ƒ‹‡†ƒ‹Ž›„›ˆ— Ǧ –‹‘‘ˆ–Š‡ƒΪȀΪƒ•‡ƒ†ƒ –•ƒ•–Š‡†”‹˜‡”ˆ‘”Ϊ‡ˆˆŽ—š‘—–‘ˆ–Š‡ ‡ŽŽǡ™Š‹ Š‹• Žƒ”‰‡Ž›†‡’‡†‡–‘’‘–ƒ••‹— Šƒ‡Ž•ǤŠ‹••›•–‡‹•‘‡‘ˆ–Š‡ƒ‹ ‘–”‹„—–‘”• –‘–Š‡‡„”ƒ‡”‡•–‹‰’‘–‡–‹ƒŽͳͷͷǤ ‘–ƒ„Ž›ǡ ™Š‹Ž‡ –Š‡ ƒ‹ †‹”‡ –‹‘ ‘ˆ Ϊ ˆŽ—š –Š”‘—‰Š’‘–ƒ••‹— Šƒ‡Ž•‹•‘—–™ƒ”†ǡ—†‡”•‘‡ ‘†‹–‹‘•Ϊ‹ˆŽ—š‹‰Š–’Žƒ›ƒ ”‘Ž‡ͳͷͷȂͳͷ͹Ǥ‘–ƒ••‹— Šƒ‡Ž•ƒ”‡Ž‹‡†–‘ƒ˜ƒ”‹‡–›‘ˆˆ— –‹‘•–Š”‘—‰Š‘—––Š‡„‘†›ǡ ‡Ǥ‰Ǥ ‘–”‘Ž ‘ˆ –Š‡ Š‡ƒ”– ”ƒ–‡ǡ •‘‘–Š —• Ž‡ ‘–”ƒ –‹‘ ƒ† ‡—”‘–”ƒ•‹––‡” ”‡Ǧ Ž‡ƒ•‡ͳͷͺǤ

’”‘–‡‹Ǧ ‘—’Ž‡†‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰’‘–ƒ••‹— Šƒ‡Ž•ȋ •Ȍ„‡Ž‘‰–‘–Š‡ˆƒǦ ‹Ž› ‘ˆ ‹™ƒ”†Ž›Ǧ”‡ –‹ˆ›‹‰ ’‘–ƒ••‹— Šƒ‡Ž• ȋ‹”Ȍͳͷͻȋ ‘’ƒ”‡ ‹‰—”‡ͶȌǤŠ‡•‡ Šƒ‡Ž•ƒ”‡ Šƒ”ƒ –‡”‹œ‡†„›ƒ‰”‡ƒ–‡”‹™ƒ”† —””‡––Šƒ‘—–™ƒ”† —””‡–†—‡–‘ ’Š›•‹ ƒŽŽ›„Ž‘ ‡†Ϊ‡ˆˆŽ—šǡ‡†‹ƒ–‡†„›‰Ϊƒ†’‘Ž›ƒ‹‡•—’‘†‡’‘Žƒ”‹œƒ–‹‘Ǥ Š‹•„Ž‘ ƒ‰‡‹•”‡˜‡”•‡†—’‘Š›’‡”’‘Žƒ”‹œƒ–‹‘ǡŽ‡ƒ†‹‰–‘Dzƒ –‹˜ƒ–‹‘dzͳͷ͸Ǥ •ƒ”‡ Žƒ••‹ˆ‹‡†ƒ••–”‘‰‹™ƒ”†”‡ –‹ˆ‹‡”•ͳͷ͸ǡͳ͸ͲǤ‹” Šƒ‡Ž•ƒ”‡ ‘’Ž‡š‡•ˆ‘”‡†„›ˆ‘—” •—„—‹–•ǡ™Š‹ ŠƒŽŽŠƒ˜‡–Š‡•ƒ‡„ƒ•‹ •–”— –—”‡ǣƒ Š•—„—‹– ‘•‹•–•‘ˆ–™‘–”ƒ•Ǧ ‡„”ƒ‡ȋȌŠ‡Ž‹ ‡•ǣŠ‡‘—–‡”ͳŠ‡Ž‹šƒ†–Š‡‹‡”ʹŠ‡Ž‹š™‹–Š–Š‡’‘”‡ Ž‘‘’ ‘–ƒ‹‹‰–Š‡•‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”‹„‡–™‡‡ȋ ‘’ƒ”‡ ‹‰—”‡Ͷǡƒ†ȌǤ•ƒŽ– „”‹†‰‡„‡Š‹†–Š‡•‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”‡†‹ƒ–‡••–ƒ„‹Ž‹–›‹–Š‡ƒŒ‘”‹–›‘ˆ‹” Šƒ‡Ž•ǡ ‹ Ž—†‹‰ •ͳͷ͸ǡͳ͸ͲǤ‹ˆˆ‡”‡–•‹–‡•‘ˆ Šƒ‡Ž‘’‡‹‰ƒ† Ž‘•‹‰Šƒ˜‡„‡‡•—‰Ǧ ‰‡•–‡†ǣ ‹”•–ǡ–Š‡„—†Ž‡ ”‘••‹‰ǡ”‡ˆ‡””‹‰–‘ƒ•‡ –‹‘™Š‡”‡–Š‡ʹ†‘ƒ‹•‘ˆ–Š‡ •—„—‹–•‹–‡”•‡ –‡ƒ”–Š‡‹–”ƒ ‡ŽŽ—Žƒ”•‹†‡‘ˆ–Š‡ Šƒ‡Žǡ™Š‹ Š„Ž‘ •–Š‡ ›–‘’Žƒ•Ǧ ‹ ’‘”‡ˆ‘”Ϊ‹‘•Ǣ•‡ ‘†ǡ–Š‡•‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”ǡ ‘–ƒ‹‹‰–Š‡ǦǦ ǦǦ ‘”ǦǦ Ǧ Ǧ ‘–‹ˆ™Š‹ Š‡†‹ƒ–‡•Ϊ•‡Ž‡ –‹˜‹–›ͳ͸Ͳǡͳ͸ͳǤ‹–Š‡”‘‡‘ˆ–Š‡‡Ž‡‡–•‹‰Š–ˆ‘”–Š‡ ’Š›•‹ ƒŽ‰ƒ–‡‘”„‘–Š‡Ž‡‡–•‹‰Š–„‡‹˜‘Ž˜‡†ͳ͸ͲǤ‹” Šƒ‡Ž•‰‡‡”ƒŽŽ›•Š‘™–™‘ –›’‡•‘ˆ‰ƒ–‹‰ǣ•Ž‘™‰ƒ–‡‘ˆ‘’‡‹‰„—”•–•ƒŽ–‡”‹‰™‹–ŠŽ‘‰ Ž‘•‡†’‡”‹‘†•ƒ†ˆƒ•– ‰ƒ–‡ ‘•‹•–‹‰‹”ƒ’‹†‘’‡‹‰ƒ† Ž‘•‹‰ǡ™Š‹ ŠŠƒ•„‡‡†‡• ”‹„‡† ƒ• DzˆŽ‹ ‡”Ǧ ‹‰dzͳͷ͸ǡͳ͸ͲǤ

ʹʹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ

•ƒ”‡ƒ Žƒ••‘ˆ‹”•–Šƒ– ƒ‹–‡”ƒ –™‹–Š éɶŠ‡–‡”‘†‹‡”‹  ’”‘–‡‹•ǡ”‡Ž‡ƒ•‡† —’‘ƒ –‹˜ƒ–‹‘‘ˆ ’”‘–‡‹Ǧ ‘—’Ž‡†”‡ ‡’–‘”•„›Ž‹‰ƒ†„‹†‹‰ǤŠ‹•‹†— ‡• ‘ˆ‘”Ǧ

ƒ–‹‘ƒŽ Šƒ‰‡•–Šƒ–Ž‡ƒ†–‘ Šƒ‡Ž‘’‡‹‰Ǥ‘”‡‡šƒ –Ž›ǡ éɶ„‹†‹‰‹‰Š–‹†— ‡ ”‘–ƒ–‹‘‘ˆ–Š‡‹‡”’‘”‡Š‡Ž‹šǤ –‹‰Š–ƒŽ•‘‹†— ‡„‡†‹‰ƒ–ƒ‰Ž› ‹‡Š‹‰‡‹ʹǤ Š‡•‡‡˜‡–•Ž‡ƒ†–‘‘’‡‹‰‘ˆ–Š‡ ›–‘•‘Ž‹ •‹†‡‘ˆ–Š‡’‘”‡ͳͷ͸ǤŠ‹•‹•–Š‡”‡•—Ž–‘ˆ †‹”‡ –‹–‡”ƒ –‹‘™‹–ŠǦ‘•–Ž‹‡Ž›Ǧ•‡˜‡”ƒŽ ›–‘•‘Ž‹ ƒ‹‘ƒ ‹†”‡•‹†—‡•‘ˆ–Š‡ ŠƒǦ

ͳ͸Ͳ ‡Ž Ǥ˜ƒ‹Žƒ„‹Ž‹–›‘ˆˆ”‡‡ éɶƒ†–Š—• ƒ –‹˜‹–›‹‰Š–„‡‘†—Žƒ–‡†„› Ƚƒ†”‡‰Ǧ

—Žƒ–‘”‘ˆ ’”‘–‡‹•‹‰ƒŽ‹‰ȋ Ȍ’”‘–‡‹•ͳͷ͸Ǥ”‡•‡ ‡‘ˆ ʹ‹•ƒŽ•‘˜‹–ƒŽˆ‘”  ƒ –‹˜‹–›ͳͷ͸ǡͳ͸ʹǤ —”–Š‡”‘”‡ǡ Šƒ‡Ž• ‘–ƒ‹‹‰ ʹƒ† Ͷ ƒ„‡ƒ –‹˜ƒ–‡†„› ‹–”ƒ ‡ŽŽ—Žƒ”ƒΪǡ•‹ ‡–Š‡•‡•—„—‹–• ‘–ƒ‹ƒƒΪ•‡•‘”ͳͷ͸ǡͳ͸͵Ȃͳ͸ͷǤ –”ƒ ‡ŽŽ—Žƒ”ƒ ‹†Ǧ ‹ˆ‹ ƒ–‹‘‹•ƒ„Ž‡–‘‹Š‹„‹–  Šƒ‡Ž•‹†‡’‡†‡–‘ˆ ’”‘–‡‹•‹‰ƒŽ‹‰ͳ͸͸Ǥ

• ƒ„‡ˆ‘—†‹ƒ˜ƒ”‹‡–›‘ˆ–‹••—‡•ǡ™Š‡”‡–Š‡› ƒ„‡ƒ –‹˜ƒ–‡†„›ƒ˜ƒ”‹‡–›‘ˆ ’”‘–‡‹Ǧ ‘—’Ž‡†”‡ ‡’–‘”•ǡ•— Šƒ•–Š‡ʹǦ—• ƒ”‹‹ ”‡ ‡’–‘”‹–Š‡Š‡ƒ”–ǡ–Š‡ȽʹǦ

ƒ†”‡‡”‰‹ ǡʹǦ†‘’ƒ‹‡ǡɊǦǡɁǦǡƒ†ɈǦ‘’‹‘‹†ǡ‰Ž—–ƒƒ–‡ƒ† ”‡ ‡’–‘”•‹‡—Ǧ ”‘•ǡ•‘‘–Š—• Ž‡ƒ† ‡ŽŽ•‘ˆ–Š‡‡†‘ ”‹‡•›•–‡ǡŽ‡ƒ†‹‰–‘‡„”ƒ‡Š›’‡”’‘Ǧ Žƒ”‹œƒ–‹‘ͳͷ͸ǡͳ͸͹Ȃͳ͹͵Ǥ Š‡› ƒ ˆ‘” ‡‹–Š‡” Š‘‘–‡–”ƒ‡”• ‘” Š‡–‡”‘–‡–”ƒ‡”• ™‹–Š ‘–Š‡” ˆƒ‹Ž›‡„‡”•ȋ ‘’ƒ”‡ ‹‰—”‡Ͷƒ†ȌǤ‘’Ž‡š ‘’‘•‹–‹‘†‡Ǧ ’‡†•‘–Š‡–‹••—‡‘” ‡ŽŽ–›’‡ͳͷ͸Ǥ ‡„”ƒ‡Ž‘ ƒŽ‹œƒ–‹‘‹•†‡’‡†‡–‘ƒ ˆ‘”™ƒ”†–”ƒˆˆ‹ ‹‰•‹‰ƒŽƒ•™‡ŽŽƒ•ƒ’‘•–•‹‰ƒŽͳ͹ͶǤ

6.2.2.1 G protein-coupled inwardly-rectifying potassium channel isoforms Š‡”‡ƒ”‡ˆ‘—”•—„ˆ‘”•‘ˆ •Ǥ ͳǡƒŽ•‘”‡ˆ‡””‡†–‘ƒ•‹”͵Ǥͳǡ‹•‡ ‘†‡†„›–Š‡ KCNJ3‰‡‡ͳͷͻǤ –• ™ƒ•ˆ‹”•–‹•‘Žƒ–‡†ˆ”‘–Š‡”ƒ–Š‡ƒ”–ͳ͹ͷǤ ͳ—•—ƒŽŽ›ˆ‘”• Š‡–‡”‘–‡–”ƒ‡”•™‹–Š‘–Š‡” ˆƒ‹Ž›‡„‡”•‹ƒ–‹˜‡ ‡ŽŽ•ͳͷ͸ǤŠ‡ ͳ‹•Š‡–Ǧ ‡”‘Ž‘‰‘—•Ž›‡š’”‡••‡†‹ƒ„•‡ ‡‘ˆ‘–Š‡”•—„—‹–•ǡ‹–”‡ƒ‹•‹–Š‡Ǥ‡„”ƒ‡ –”ƒˆˆ‹ ‹‰ ƒ„‡”‡ ‘•–‹–—–‡†„› ‘‡š’”‡••‹‘™‹–Š ʹƒ† Ͷͳ͹ͶǤ

ʹȋ‹”͵ǤʹȌ‹•‡ ‘†‡†„›–Š‡KCNJ6‰‡‡ͳͷͻǤ – ‘’”‹•‡••‡˜‡”ƒŽ‹•‘ˆ‘”•‘ˆ†‹ˆǦ ˆ‡”‡–Ž‡‰–Š•ǡ™Š‹ Šƒ”‡–Š‡’”‘†— –‘ˆƒŽ–‡”ƒ–‹˜‡•’Ž‹ ‹‰ƒ†Ȁ‘”†‹ˆˆ‡”‡–‹ƒŽ–”ƒǦ • ”‹’–‹‘ͳͷ͸ǡͳ͹͸ǡͳ͹͹Ǥ ʹ ƒ„‡ˆ‘—†‹ƒ˜ƒ”‹‡–›‘ˆ–‹••—‡••— Šƒ•–Š‡„”ƒ‹ǡ’‹–—‹–ƒ”› ‰Žƒ†ǡ’ƒ ”‡ƒ•ƒ†–‡•–‹•ͳͷ͸ǡͳ͹ͺȂͳͺͳǤŠ‡›ƒ”‡‘ˆ–‡ ‘Ǧ‡š’”‡••‡†™‹–Š‘–Š‡” •—„Ǧ —‹–•ƒ†Šƒ˜‡„‡‡†‡• ”‹„‡†–‘ˆ‘”Š‡–‡”‘–‡–”ƒ‡”•™‹–Š‘–Š‡” ˆƒ‹Ž›‡Ǧ „‡”•ͳͷ͸ǡͳ͹ͺǡͳͺʹȂͳͺͷǤ ‘™‡˜‡”ǡ–Š‡›ƒŽ•‘„—‹Ž†Š‘‘–‡–”ƒ‡”•‹•‘‡ ‡ŽŽ•ͳͷ͸ǡͳͺͲǡͳͺʹǤ

ʹ͵ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ



&ŝŐƵƌĞϰ͘/ŶǁĂƌĚůLJͲƌĞĐƚŝĨLJŝŶŐƉŽƚĂƐƐŝƵŵĐŚĂŶŶĞůƐ͘Ϳ<ŝƌƐƵďƵŶŝƚƐĐŽŶƐŝƐƚŽĨƚǁŽƚƌĂŶƐŵĞŵďƌĂŶĞƐƵďƵŶŝƚƐ ĂŶĚĂƉŽƌĞĚŽŵĂŝŶ͘^ĐŚĞŵĂƚŝĐĚĞƉŝĐƚŝŽŶĂĚĂƉƚĞĚĨƌŽŵŝĐŚĞƚ͕,ĂĂƐƐĂŶĚ:ĂŶ͕ϮϬϬϯϭϲϬ͘ͿƌLJƐƚĂůƐƚƌƵĐƚƵƌĞŽĨ н ƚŚĞŽĨƚŚĞƚĞƚƌĂŵĞƌŝĐĂƐƐĞŵďůLJŽĨ'/Z<ϮŝŶĐŽŵƉůĞdžǁŝƚŚW/WϮĂŶĚEĂ ŽďƚĂŝŶĞĚĨƌŽŵƉƌŽƚĞŝŶĚĂƚĂďĂƐĞ;W /͗ϯ^z͕ƉƌŽǀŝĚĞĚďLJtŚŽƌƚŽŶĞƚĂů͕͘ϮϬϭϭϴϲͿ͘ͿdƌĂŶƐŵĞŵďƌĂŶĞǀŝĞǁŽĨƚŚĞĐƌLJƐƚĂůƐƚƌƵĐƚƵƌĞŽĨƚĞƚƌĂŵĞƌŝĐ н '/Z<ϮŝŶĐŽŵƉůĞdžǁŝƚŚW/WϮĂŶĚEĂ ŽďƚĂŝŶĞĚĨƌŽŵƉƌŽƚĞŝŶĚĂƚĂďĂƐĞ;W/͗ϯ^z͕ƉƌŽǀŝĚĞĚďLJtŚŽƌƚŽŶĞƚ Ăů͕͘ϮϬϭϭϭϴϲͿ͘ͿŝĨĨĞƌĞŶƚĐůĂƐƐĞƐŽĨ<ŝƌĐŚĂŶŶĞůƐĂŶĚƚŚĞŝƌŵĞŵďĞƌƐϭϱϲ͘ 

‡•‹†‡•ƒ‡š’‘”–•‹‰ƒŽƒ†ƒ’‘•–•‹‰ƒŽ’”‘‘–‹‰•—”ˆƒ ‡‡š’”‡••‹‘ǡ ʹ ‹‰Š– ‘–ƒ‹ƒ‘–‹ˆ’”‘‘–‹‰ Šƒ‡Ž‹–‡”ƒŽ‹œƒ–‹‘ǡ™Š‹ Š‘†—Žƒ–‡•‹–•‡Ǧ „”ƒ‡ƒ„—†ƒ ‡ͳ͹ͶǤ

͵Ȁ‹”͵Ǥ͵ȀKCNJ9™ƒ•ˆ‹”•–‹†‡–‹ˆ‹‡†‹ ˆ”‘–Š‡—”‹‡„”ƒ‹ͳͷͻǡͳͺͳǤ –Šƒ• „‡‡•—‰‰‡•–‡†–‘ˆ‘”Š‡–‡”‘–‡–”ƒ‡”•™‹–Š‘–Š‡” •—„—‹–•ͳͷ͸ǡͳͺͶǡͳͺ͹Ǥ ‘™‡˜‡”ǡ ‘ˆŽ‹ –‹‰ ”‡•—Ž–• Šƒ˜‡ „‡‡ ’—„Ž‹•Š‡† ™‹–Š ”‡‰ƒ”† –‘ ˆ— –‹‘ƒŽ‹–›‘ˆ–Š‡•‡ ŠƒǦ ‡Ž•ͳͷ͸Ǥ ͵Žƒ •ƒˆ‘”™ƒ”†–”ƒˆˆ‹ ‹‰•‹‰ƒŽ„—– ‘–ƒ‹•ƒ‘–‹ˆˆ‘”Ž›•‘•‘‡ –ƒ”‰‡–‹‰ͳ͹ͶǤ‘‡š’”‡••‹‘‘ˆ‘–Š‡” ͳǦ ‘–ƒ‹‹‰Š‡–‡”‘†‹‡”•™‹–Š ͵‹‰Š– ’”‘‘–‡ –Š‡‹”  ”‡–‡–‹‘ ƒ† –Š—• ”‡†— ‡ ‡„”ƒ‡ ‡š’”‡••‹‘ ƒ†Ȁ‘” ƒ –‹˜Ǧ ‹–›ͳͷ͸ǡͳ͹ͶǡͳͺͷǤ

ʹͶ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ 6.2.2.1.1Kir3.4/GIRK4/KCNJ5 Ͷȋ‹”͵ǤͶȌ‹•‡ ‘†‡†„›KCNJ5ͳͷͻǤ –™ƒ•ˆ‹”•–‹†‡–‹ˆ‹‡††—‡–‘‹–• ‘Ǧ‹—‘’”‡Ǧ ‹’‹–ƒ–‹‘™‹–Š ͳ‹’”‡’ƒ”ƒ–‹‘•‘ˆ–Š‡„‘˜‹‡ƒ–”‹ƒŽ‡„”ƒ‡ͳͺͺǤ –ˆ‘”•Š‡–Ǧ ‡”‘–‡–”ƒ‡”•™‹–Š ͳ‹ƒͳǣͳ”ƒ–‹‘ͳͺͻǤ ‘™‡˜‡”ǡ‹–ƒŽ•‘•‡‡•–‘‡š‹•–‹ƒŠ‘‘Ǧ –‡–”ƒ‡”‹ ˆ‘”‹–Š‡„‘˜‹‡ƒ–”‹—ͳͻͲǤ Ͷ’”‘–‡‹™ƒ•ƒŽ•‘‹†‡–‹ˆ‹‡†‹–Š‡ƒš‘ –‡”‹ƒŽ•‹–Š‡”ƒ–„”ƒ‹ͳͻͳǤ ‡–‡”‘†‹‡”•‘ˆ Ͷƒ† ʹŠƒ˜‡„‡‡‹’Ž‹ ƒ–‡† –‘’Žƒ›ƒ”‘Ž‡‹–Š‡‘†—Žƒ–‹‘‘ˆŠ‘”‘‡”‡Ž‡ƒ•‡ˆ”‘’ƒ ”‡ƒ–‹ ‹•Ž‡– ‡ŽŽ•ͳͷ͸ǡͳ͹ͺǤ

—• ƒ”‹‹ ΪȋŠȌ Šƒ‡Ž —””‡–•ǡŽ‹‡Ž›‰‡‡”ƒ–‡†„› ͳȀͶ Šƒ‡Ž•ǡ‹‰Š–„‡ ‹˜‘Ž˜‡†‹ƒ–”‹ƒŽˆ‹„”‹ŽŽƒ–‹‘ͳͷ͸ǡͳͻʹǤ Ͷ‘ ‘—–‹ ‡•Š‘™Ž‡••˜ƒ”‹ƒ„‹Ž‹–›‹–Š‡‹” Š‡ƒ”–”ƒ–‡ƒ–”‡•–ƒ†ƒˆ–‡”•–‹—Žƒ–‹‘–Šƒ™‹Ž†–›’‡‹ ‡ǡ•—‰‰‡•–‹‰–Šƒ– Ͷ‹• ‹˜‘Ž˜‡†‹—”‹‡Š‡ƒ”–”ƒ–‡”‡‰—Žƒ–‹‘ͳͻ͵ǤŠ‡•‡‹ ‡ƒ”‡ƒŽ•‘’”‘‡–‘†‡˜‡Ž‘’Žƒ–‡Ǧ ‘•‡–‘„‡•‹–›ǡ•—‰‰‡•–‹‰ƒ”‘Ž‡‘ˆ Ͷ‹ƒ‹–ƒ‹‹‰‡‡”‰›„ƒŽƒ ‡ƒ†”‡‰—Žƒ–‹‘ ‘ˆ„‘†›™‡‹‰Š–ͳͻͶǤ‡Šƒ˜‹‘”ƒŽ•–—†‹‡•‘ˆ Ͷ‘ ‘—–‹ ‡‹‰Š–‹’Ž›•Ž‹‰Š–Ž›†‡Ǧ ”‡ƒ•‡†ƒ„‹Ž‹–‹‡•‹•’ƒ–‹ƒŽŽ‡ƒ”‹‰ƒ†‡‘”›ǡŠ‹–‹‰ƒ–ƒ‹˜‘Ž˜‡‡–‘ˆ Ͷ‹ –Š‡•‡ˆ— –‹‘•ͳͻͷǤKCNJ5Ž‘••Ǧ‘ˆǦˆ— –‹‘—–ƒ–‹‘ȋ ͵ͺ͹ȌŠƒ•„‡‡‹†‡–‹ˆ‹‡†‹ƒ ˆƒ‹Ž›™‹–ŠŽ‘‰•›†”‘‡ͳͻ͸Ǥ —”–Š‡”‘”‡ Ͷ‹•‡š’”‡••‡†‹–Š‡Š—ƒƒ†Ǧ ”‡ƒŽ ƒ•™‡ŽŽƒ•–Š‡ƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ʹͻͷͳͻ͹ǡͳͻͺǤ ‘™‡˜‡”ǡˆ— –‹‘ƒŽ‹–› ‘ˆƒ–‹˜‡ǡ„—–‘–‘ˆ‘˜‡”‡š’”‡••‡†ǡ Ͷ Šƒ‡Ž•‹–Š‹• ‡ŽŽŽ‹‡Šƒ•„‡‡†‹•Ǧ ’—–‡†ͳͻͻǤ—–ƒ–‹‘•‹‘” Ž‘•‡–‘–Š‡ ǦǦ •‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”Šƒ˜‡„‡‡ˆ‘—†‹’ƒ–‹‡–• ™‹–Šˆƒ‹Ž‹ƒŽˆ‘”•‘ˆŠ›’‡”ƒŽ†‘•–‡”‘‹•ƒ†ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒȋ•‡‡ •‡ –‹‘•͸Ǥ͵ǤʹǤͳǤͳƒ†͸Ǥ͵ǤʹǤʹǤ͵ȌǤ

–—†‹‡•‹–Š‡ƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ͳͷ•Š‘™–Šƒ–KCNJ5‘˜‡”‡š’”‡••‹‘‹Ǧ ”‡ƒ•‡•‡„”ƒ‡Š›’‡”’‘Žƒ”‹œƒ–‹‘ƒ†”‡†— ‡•„ƒ•ƒŽƒ•™‡ŽŽƒ•‰ Ǧ•–‹—Žƒ–‡† ƒʹΪ‹ˆŽ—šǡCYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Ǥ‹‹Žƒ”‡ˆˆ‡ –•‘‰ Ǧ ‡†‹ƒ–‡† †‡’‘Žƒ”‹œƒ–‹‘ǡ CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ ‘—Ž†„‡ ‘„•‡”˜‡†—’‘–”‡ƒ–‡–™‹–Š  Šƒ‡Žƒ –‹˜ƒ–‘”ƒ”‹‰‹ʹͲͲǡʹͲͳǤ ‘™‡˜‡”ǡKCNJ5 ‘ †‘™†‹†‘–Šƒ˜‡ƒ›‡ˆˆ‡ –•ǡ™Š‹ Š–Š‡ƒ—–Š‘”•ƒ––”‹„—–‡†–‘ ‘’‡•ƒ–‹‘„› ‘–Š‡”’‘–ƒ••‹— Šƒ‡Ž•Ǥ —”–Š‡”‘”‡ǡKCNJ5‡š’”‡••‹‘™ƒ•”‡†— ‡†„›‰ •–‹Ǧ —Žƒ–‹‘‘”–”‡ƒ–‡–™‹–ŠƒƒʹΪ‹‘‘’Š‘”‡ǤŠ‡•‡”‡•—Ž–•‹’Ž‹ ƒ–‡ƒ’‘••‹„Ž‡”‘Ž‡‘ˆ  ͷƒ•ƒ‡‰ƒ–‹˜‡”‡‰—Žƒ–‘”‘ˆ‰ Ǧ‡†‹ƒ–‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ ǡƒ –Ǧ ‹‰–Š”‘—‰Š‹–‡”ˆ‡”‡ ‡™‹–Š‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ƒ†ƒʹΪ‹ˆŽ—šǤKCNJ5†‘™Ǧ ”‡‰—Žƒ–‹‘ ‹‰Š– ‘•–‹–—–‡ ƒ ’‘•‹–‹˜‡ ˆ‡‡†„ƒ ǡ ‡Šƒ ‹‰ ‰ Ǧ‡†‹ƒ–‡† ƒŽ†‘•–‡Ǧ ”‘‡’”‘†— –‹‘ʹͲͳ.

ʹͷ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‡˜‡”ƒŽ‹Š‹„‹–‘”•‘ˆ ͶǦ ‘–ƒ‹‹‰ Šƒ‡Ž•Šƒ˜‡„‡‡†‡• ”‹„‡†ǣŠ‡„‡‡˜‡‘Ǧ †‡”‹˜‡†’‘–ƒ••‹— Šƒ‡Ž‹Š‹„‹–‘”–‡”–‹ƒ’‹‹•ƒ„Ž‡–‘‹Š‹„‹– ͳȀͶ Šƒ‡Ž•ʹͲʹǤ –—†‹‡•‹ ʹͻͷ ‡ŽŽ‘˜‡”‡š’”‡••‹‰KCNJ5 ™‹Ž†–›’‡ƒŽ•‘•—‰‰‡•–Š‘‘–‡–”ƒ‡”‹Ǧ

Š‹„‹–‹‘ʹͲ͵Ǥ —”–Š‡”‘”‡ǡ–Š‡ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡”˜‡”ƒ’ƒ‹Ž„Ž‘ •Š —””‡–• ‹–Š‡Š‡ƒ”–ǡ™Š‹ Šƒ”‡Ž‹‡Ž›‰‡‡”ƒ–‡†„› ͳȀͶ Šƒ‡Žƒ –‹˜‹–›ͳͷ͸ǡʹͲͶǤ‹‡ˆ‘”‘•– ‘–Š‡” ‹” Šƒ‡Ž•ǡ ‹‘”‰ƒ‹  „Ž‘ ƒ‰‡ ‘ˆ Ͷ ƒ „‡ ƒ Š‹‡˜‡†™‹–ŠƒʹΪƒ† •Ϊȋ ‘’ƒ”‡‡Ǥ‰Ǥͳͷ͸ǡͳͻ͹ǡʹͲͷȌǤŠƒ”ƒ ‘Ž‘‰‹ ’”‘’‡”–‹‡•‘ˆ Ͷ—–ƒ– Šƒ‡Ž•™‹ŽŽ „‡†‡• ”‹„‡†‹•‡ –‹‘͸Ǥ͵ǤʹǤͳǤͳǤ Š‹„‹–‹‘‘ˆ—–ƒ– Ͷ Šƒ‡Ž•™Š‹Ž‡ƒ˜‘‹†‹‰ ™‹Ž†–›’‡„Ž‘ ƒ‰‡–‘’”‡˜‡–•›’–‘•ƒ••‘ ‹ƒ–‡†™‹–ŠŽ‘••‘ˆˆ— –‹‘™‹ŽŽ„‡ƒ ‹’‘”–ƒ––‘’‹ ‘ˆ–Š‹•™‘”Ǥ

”‘Š‡”‡‘ǡ  Šƒ‡Ž•ƒ†–Š‡‹”•—„—‹–•™‹ŽŽ„‡”‡ˆ‡””‡†–‘„›–Š‡‰‡‡ƒ‡ ‘ˆ–Š‡”‡•’‡ –‹˜‡•—„—‹–‘”•—„—‹–•ȋ‡Ǥ‰Ǥ‹”͵ǤͶƒ† Ͷƒ”‡ ƒŽŽ‡† ͷȌǤ

6.3 Hypertension Š‡–‡”ƒ”–‡”‹ƒŽŠ›’‡”–‡•‹‘”‡ˆ‡”•–‘ƒ‡†‹ ƒŽ ‘†‹–‹‘‹™Š‹ Š–Š‡’”‡••—”‡‹ –Š‡ƒ”–‡”‹ƒŽ˜ƒ• —Žƒ”•›•–‡‹• Š”‘‹ ƒŽŽ›‹ ”‡ƒ•‡†Ǥ –Š‡‹”ʹͲͳ͵‰—‹†‡Ž‹‡•ˆ‘”–Š‡ ƒƒ‰‡‡–‘ˆƒ”–‡”‹ƒŽŠ›’‡”–‡•‹‘ǡ–Š‡—”‘’‡ƒ‘ ‹‡–›‘ˆ ›’‡”–‡•‹‘ȋ Ȍƒ† —”‘’‡ƒ‘ ‹‡–›‘ˆƒ”†‹‘Ž‘‰›ȋȌ Žƒ••‹ˆ›ƒ•›•–‘Ž‹ „Ž‘‘†’”‡••—”‡ηͳͶͲ ‰‘” ƒ†‹ƒ•–‘Ž‹ „Ž‘‘†’”‡••—”‡ηͻͲ ‰ƒ•Š›’‡”–‡•‹˜‡™Š‡‡ƒ•—”‡†‹ƒ†‘ –‘”ǯ• ‘ˆˆ‹ ‡ʹͲ͸Ǥ –™ƒ••—‰‰‡•–‡†–Šƒ–‹–Š‡›‡ƒ”ʹͲͲͲʹ͸ǤͶΨ‘ˆ–Š‡™‘”Ž†’‘’—Žƒ–‹‘•—ˆˆ‡”‡† ˆ”‘Š›’‡”–‡•‹‘™‹–Šƒ’”‡†‹ –‡†–‡†‡ ›–‘™ƒ”†•‹ ”‡ƒ•‡ȋʹͻǤʹΨ‹ʹͲʹͷȌǤŠ‹Ž‡ –Š‡†‹•‡ƒ•‡ƒŽ•‘ƒˆˆ‡ –•ƒ‰”‡ƒ–—„‡”‘ˆ’‡‘’Ž‡‹†‡˜‡Ž‘’‹‰ ‘—–”‹‡•ǡ‹–Šƒ•ƒ‡•Ǧ ’‡ ‹ƒŽŽ›Š‹‰Š’”‡˜ƒŽ‡ ‡‹–Š‡™‡•–‡”‹†—•–”‹ƒŽ‹œ‡† ‘—–”‹‡•ʹͲ͹Ǥ•–—†›ˆ”‘ʹͲͲ͵ •—‰‰‡•–•–Šƒ–ʹ͹Ǥ͸Ψ‘ˆ‘”–Š‡”‹ ƒ•‘˜‡”–Š‡ƒ‰‡‘ˆ͵ͷƒ”‡Š›’‡”–‡•‹˜‡Ǥ ‘” ‡”Ǧ ƒ›ǡ–Š‡’‡” ‡–ƒ‰‡‘ˆƒˆˆ‡ –‡†‹†‹˜‹†—ƒŽ•™ƒ•Š‹‰Š‡”–Šƒ–Š‡—”‘’‡ƒƒ˜‡”ƒ‰‡ ȋͷͷǤ͵Ψ ˜‡”•—• ͶͶǤʹΨǡ ”‡•’‡ –‹˜‡Ž›ȌʹͲͺǤ ‘•‹†‡”‹‰ †‹ˆˆ‡”‡– •–—†‹‡•ǡ –Š‡   ’”‘Ǧ ’‘•‡†‹ʹͲͳ͵–Šƒ–͵ͲǦͶͷΨ‘ˆ–Š‡‰‡‡”ƒŽ—”‘’‡ƒ’‘’—Žƒ–‹‘‹‰Š–„‡Š›’‡”–‡Ǧ •‹˜‡ʹͲ͸Ǥ‘”Ž†™‹†‡ǡ–Š‡’‡” ‡–ƒ‰‡‘ˆƒˆˆ‡ –‡†‹†‹˜‹†—ƒŽ•‹ ”‡ƒ•‡•™‹–Šƒ‰‡ǤŠ‡‘˜‡”Ǧ ƒŽŽ’‡” ‡–ƒ‰‡‘ˆƒˆˆ‡ –‡†‡‹•Š‹‰Š‡”ƒ–ƒ›‘—‰‡”ƒ‰‡ǡ™Š‡”‡ƒ•–Š‡’”‘’‘”–‹‘‘ˆ Š›’‡”–‡•‹˜‡™‘‡‹•Žƒ”‰‡”ƒ–ƒ‘Ž†‡”ƒ‰‡Ǥ ‘™‡˜‡”ǡ–Š‡‘˜‡”ƒŽŽ†‹ˆˆ‡”‡ ‡„‡–™‡‡ ƒŽ‡ƒ†ˆ‡ƒŽ‡ƒ’’‡ƒ”•–‘„‡•ƒŽŽƒ†•‡š’”‡˜ƒŽ‡ ‡••‡‡•–‘†‹ˆˆ‡”„‡–™‡‡”‡Ǧ ‰‹‘•ʹͲ͹Ǥ

›’‡”–‡•‹‘‹•ƒ••‘ ‹ƒ–‡†™‹–Šƒ‹ ”‡ƒ•‡†”‹•‘ˆ ƒ”†‹‘˜ƒ• —Žƒ”ƒ† ‡”‡„”‘˜ƒ• —Ǧ Žƒ”ˆƒ–ƒŽ‹–›ǡƒ–Š‡”‘• Ž‡”‘•‹•„‡‹‰ƒ‹’‘”–ƒ–ˆƒ –‘”–Šƒ–”ƒ‹•‡•–Š‡”‹•ˆ‘” ‘”‘ƒ”›

ʹ͸ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ Š‡ƒ”–†‹•‡ƒ•‡ǡ•–”‘‡ƒ†›‘ ƒ”†‹ƒŽ‹ˆƒ” –‹‘ʹͲͻȂʹͳ͵Ǥ • Š‡‹ Š‡ƒ”–†‹•‡ƒ•‡ƒ† ‡”Ǧ ‡„”‘˜ƒ• —Žƒ”†‹•‡ƒ•‡ƒ”‡ƒ‘‰–Š‡Ž‡ƒ†‹‰ ƒ—•‡•‘ˆ†‡ƒ–Š‹Š‹‰ŠǦ‹ ‘‡ ‘—–”‹‡• ȋʹ͹ǤʹΨ‘ˆ†‡ƒ–Š•‹ʹͲͲͳȌʹͳͶǤ ›’‡”–‡•‹‘ ƒƒŽ•‘†ƒƒ‰‡–Š‡Š‡ƒ”–—• Ž‡ǡŽ‡ƒ†‹‰ –‘Š›’‡”–‡•‹˜‡Š‡ƒ”–†‹•‡ƒ•‡ǡ™Š‹ Š ƒ‹ Ž—†‡Š‡ƒ”–ˆƒ‹Ž—”‡ʹͳͷǤ‘–Š‡””‹•ƒ••‘ ‹Ǧ ƒ–‡†™‹–ŠŠ›’‡”–‡•‹‘‹•”‡ƒŽˆƒ‹Ž—”‡ ƒ—•‡†„›†ƒƒ‰‡–‘–Š‡„Ž‘‘†˜‡••‡Ž•‹–Š‡ ‹†‡›•ʹͳ͸Ǥ‘”‡‘˜‡”ǡŠ›’‡”–‡•‹‘ ƒŽ‡ƒ†–‘˜‹•—ƒŽ‹’ƒ‹”‡–†—‡–‘†ƒƒ‰‡‘ˆ „Ž‘‘†˜‡••‡Ž•‹–Š‡”‡–‹ƒȋŠ›’‡”–‡•‹˜‡”‡–‹‘’ƒ–Š›Ȍʹͳ͹Ǥ

ˆ–Š‡ ƒ—•‡‘ˆŠ›’‡”–‡•‹‘ ƒ‘–„‡‹†‡–‹ˆ‹‡†ǡ‹–‹•”‡ˆ‡””‡†–‘ƒ•‡••‡–‹ƒŽŠ›’‡”–‡Ǧ •‹‘ǡ‹†‹‘’ƒ–Š‹ Š›’‡”–‡•‹‘ǡ‘”’”‹ƒ”›Š›’‡”–‡•‹‘Ǥˆˆ‡ –‹‰‘˜‡”ͻͲΨ‘ˆŠ›’‡”Ǧ –‡•‹˜‡’ƒ–‹‡–•ǡ–Š‹•‹•–Š‡‘•–’”‡˜ƒŽ‡–ˆ‘”‘ˆ–Š‡†‹•‡ƒ•‡ʹͳͺǤ –‹••—’’‘•‡†–Šƒ– „‘–Š‰‡‡–‹ ƒ†‡˜‹”‘‡–ƒŽˆƒ –‘”•ǡ•— Šƒ•‘„‡•‹–›ǡŠ‹‰Š•‘†‹—‹–ƒ‡ǡŽƒ ‘ˆ ‡š‡” ‹•‡ƒ†‡š ‡••‹˜‡ƒŽ ‘Š‘Ž ‘•—’–‹‘’Žƒ›ƒ”‘Ž‡‹–Š‡†‡˜‡Ž‘’‡–‘ˆ‡••‡–‹ƒŽ Š›’‡”–‡•‹‘ʹͳͻǡʹʹͲǤ ›’‡”–‡•‹‘ ƒ—•‡†„›‘™—†‡”Ž›‹‰ˆƒ –‘”•‹•”‡ˆ‡””‡†–‘ƒ• •‡ ‘†ƒ”›Š›’‡”–‡•‹‘Ǥƒ—•‡• ƒ ‘•‹•–‘ˆƒ˜ƒ”‹‡–›‘ˆ”‡ƒŽ‘”‡†‘ ”‹‡†‹•‘”Ǧ †‡”•ʹͲ͸Ǥ

Š‹–‡ ‘ƒ–Š›’‡”–‡•‹‘†‡• ”‹„‡•ƒ ‘†‹–‹‘‹™Š‹ Š„Ž‘‘†’”‡••—”‡‹•‡Ž‡˜ƒ–‡†‹ƒ Ž‹‹ ƒŽ•‡––‹‰ǡ™Š‹Ž‡–Š‡’ƒ–‹‡–‹•‘”‘–‡•‹˜‡‹‘—–Ǧ‘ˆǦ–Š‡Ǧ‘ˆˆ‹ ‡‡ƒ•—”‡‡–•Ǥ Š‡ ‘–”ƒ•–‹‰‡ˆˆ‡ –Ǧ‘”ƒŽ„Ž‘‘†’”‡••—”‡‹‹Ǧ‘ˆˆ‹ ‡‡ƒ•—”‡‡–•ƒ†Š›’‡”Ǧ –‡•‹‘‹ƒ†‘‡•–‹ •‡––‹‰Ǧ‹•”‡ˆ‡””‡†–‘ƒ•ƒ•‡†Š›’‡”–‡•‹‘ʹͲ͸Ǥ

6.3.1 Antihypertensives ‡‹’‘”–ƒ–ƒ•’‡ –‘ˆ–Š‹•™‘”‹•–‘’”‘˜‹†‡‡™‹’—Ž•‡•ˆ‘”–ƒ”‰‡–‡†–”‡ƒ–‡– •–”ƒ–‡‰‹‡•‹’ƒ–‹‡–•™‹–Š‘™—†‡”Ž›‹‰ ƒ—•‡•‘ˆŠ›’‡”–‡•‹‘ǤŠ‡”‡ˆ‘”‡ǡƒ‰‡Ǧ ‡”ƒŽ‹œ‡†‘˜‡”˜‹‡™ƒ„‘—– —””‡–ƒ’’”‘ƒ Š‡•‹•‘ˆ‹–‡”‡•–ǤŠ‡”‡ƒ”‡†‹ˆˆ‡”‡– ‘‘ Žƒ••‡•‘ˆ ‘’‘—†••—‹–ƒ„Ž‡–‘–”‡ƒ–Š›’‡”–‡•‹‘ǡ™Š‹ Š ƒ„‡—•‡†ƒŽ‘‡‘”‹ ‘„‹ƒ–‹‘ǤŠ‡›–ƒ”‰‡–†‹ˆˆ‡”‡–‡Ž‡‡–•‘ˆ„Ž‘‘†’”‡••—”‡Š‘‡‘•–ƒ•‹•Ǥ‡ŽŽ‡•Ǧ –ƒ„Ž‹•Š‡†ˆƒ‹Ž‹‡•‘ˆƒ–‹Š›’‡”–‡•‹˜‡•ƒ”‡‹Š‹„‹–‘”•ǡƒ‰‹‘–‡•‹”‡ ‡’–‘”„Ž‘ Ǧ ‡”•ǡ„‡–ƒ„Ž‘ ‡”•ǡ†‹—”‡–‹ •ǡƒ•™‡ŽŽƒ• ƒŽ ‹—ƒ–ƒ‰‘‹•–•ʹͲ͸Ǥ

‹Š‹„‹–‘”•ƒ†ƒ‰‹‘–‡•‹”‡ ‡’–‘”„Ž‘ ‡”•†‹”‡ –Ž›‹–‡”ˆ‡”‡™‹–Š–Š‡ǡ–Š‡ ˆ‘”‡”„›‹Š‹„‹–‹‰–Š‡ǡ–Š—•Ž‡ƒ†‹‰–‘”‡†— ‡†’”‘†— –‹‘‘ˆ‰ ƒ†–Š‡Žƒ––‡”

„›‹’‡†‹‰ƒ –‹˜ƒ–‹‘‘ˆ–Š‡ͳ”‡ ‡’–‘”ʹʹͳǤŠ‹Ž‡‹Š‹„‹–‘”•ƒ’’‡ƒ”–‘„‡‘”‡ ‡ˆˆ‡ –‹˜‡–Šƒƒ‰‹‘–‡•‹”‡ ‡’–‘”„Ž‘ ‡”•‹’”‡˜‡–‹‰›‘ ƒ”†‹ƒŽ‹ˆƒ” –‹‘ǡ–Š‡› •‡‡–‘„‡Ž‡••‡ˆˆ‡ –‹˜‡–Šƒ‘–Š‡” Žƒ••‡•‘ˆŠ›’‡”–‡•‹˜‡•‹ ‘—–‡”ƒ –‹‰•–”‘‡ʹͲ͸Ǥ

ʹ͹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‡–ƒ „Ž‘ ‡”• ƒ”‡ ‘’‡–‹–‹˜‡ ‹Š‹„‹–‘”• ‘ˆ ƒ†”‡‡”‰‹  „‡–ƒ ”‡ ‡’–‘”•Ǥ Š‡‹” Žƒ••‹  ƒ‹ƒ–‹Š›’‡”–‡•‹˜‡‘†‡‘ˆƒ –‹‘‹•”‡†— –‹‘‘ˆ ƒ”†‹ƒ ‘—–’—–ǡƒŽ–Š‘—‰Š•‘‡ †”—‰•‘ˆ–Š‹• Žƒ••ƒ‹Ž›ƒ ––Š”‘—‰Š”‡†— –‹‘‘ˆ˜ƒ• —Žƒ””‡•‹•–ƒ ‡ʹʹʹǤ‡•’‹–‡–Š‡‹” ”‡’‘”–‡†‹ˆ‡”‹‘”‹–›–‘•‘‡‘–Š‡”ˆƒ‹Ž‹‡•‘ˆƒ–‹Š›’‡”–‡•‹˜‡•‹ƒ‡Ž‹‘”ƒ–‹‰ ‡”–ƒ‹ •‡ ‘†ƒ”› ‘’Ž‹ ƒ–‹‘•Ž‹‡•–”‘‡‹•‘‡•–—†‹‡•ǡ–Š‡ Ȁ•–‹ŽŽ ‘•‹†‡”„‡–ƒ „Ž‘ ‡”•ƒ‘’–‹‘ˆ‘”–Š‡–Š‡”ƒ’›‘ˆŠ›’‡”–‡•‹‘ʹͲ͸Ǥ

‹—”‡–‹ • ƒ”‡ ‰‡‡”ƒŽŽ› ƒ ˆ‹”•– Š‘‹ ‡ ‘ˆ ‡†‹ ƒ–‹‘ ™Š‡ ‹– ‘‡• –‘ Š›’‡”–‡•‹‘ –”‡ƒ–‡–ʹͲ͸Ǥ‹—”‡–‹ •’”‘‘–‡ƒΪƒ†™ƒ–‡”‡š ”‡–‹‘„›–Š‡‹†‡›ǡ–Š—•†‡ ”‡ƒ•Ǧ ‹‰’Žƒ•ƒ˜‘Ž—‡ƒ† ‘•‡“—‡–Ž›„Ž‘‘†’”‡••—”‡ʹʹ͵ǡʹʹͶǤŠ‹ƒœ‹†‡†‹—”‡–‹ •’”‡˜‡– ƒΪ”‡ƒ„•‘”’–‹‘„›‹Š‹„‹–‹‰–Š‡‹–Š‡†‹•–ƒŽ ‘˜‘Ž—–‡†–—„—Ž‡‘ˆ–Š‡‹†‡›ʹʹͷǤ ‘–Š‡” Žƒ••‘ˆ†‹—”‡–‹  ‘’‘—†•ƒ”‡’‘–ƒ••‹—•’ƒ”‹‰†‹—”‡–‹ ••— Šƒ•–Š‡‹Ǧ ‡”ƒŽ‘ ‘”–‹ ‘‹†”‡ ‡’–‘”ƒ–ƒ‰‘‹•–•’‹”‘‘Žƒ –‘‡ǤŠ‡•‡ƒ”‡ƒ‡ˆˆ‡ –‹˜‡–”‡ƒ–‡–‹ •—„Œ‡ –•™‹–ŠŠ›’‘ƒŽ‡‹ƒʹͲ͸ǡʹʹ͸Ǥ

ƒŽ ‹—ƒ–ƒ‰‘‹•–•ƒ”‡’Šƒ”ƒ ‡—–‹ ƒŽ•–Šƒ–ƒ”‡ƒ„Ž‡–‘„Ž‘ †‹ˆˆ‡”‡– Žƒ••‡•‘ˆ˜‘Ž–Ǧ ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•ǡ™Š‡”‡ƒ•ƒ› Š‹‡ˆŽ›‘”‡š Ž—•‹˜‡Ž›ƒ –‘Ǧ–›’‡ ŠƒǦ ‡Ž•ǡ™‹–Š˜‡”ƒ’ƒ‹Ž„‡‹‰ƒ’”‘‹‡–‡šƒ’Ž‡ͳʹ͵ǡʹʹ͹ǡʹʹͺǤŠ‡› ƒ—•‡˜ƒ•‘†‹Žƒ–‹‘ƒ† ”‡†— ‡ ‘–”ƒ –‹Ž‹–›‘ˆ–Š‡Š‡ƒ”–ʹʹ͹ǡʹʹͺǤ —”–Š‡”‘”‡ǡ ‘’‘—†•‘ˆ–Š‹• Žƒ••Šƒ˜‡„‡‡ ”‡’‘”–‡†–‘”‡†— ‡ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•‹’ƒ–‹‡–•ǡŽ‹‡Ž›–Š”‘—‰Š†‹”‡ –‹–‡”ˆ‡”‡ ‡ ™‹–ŠƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ƒ†”‡ƒŽ‰Žƒ†ͳͳͲǡʹʹͻǡʹ͵ͲǤ–Š‡‘‡Šƒ†ǡ ƒŽ ‹— ƒ–ƒ‰‘‹•–•ƒ›„‡•Ž‹‰Š–Ž›‘”‡‡ˆˆ‡ –‹˜‡‹’”‡˜‡–‹‰•–”‘‡–Šƒ‘–Š‡” Žƒ••‡•‘ˆ ƒ–‹Š›’‡”–‡•‹˜‡•ǡ‘–Š‡‘–Š‡”Šƒ†ǡ–Š‡‹”‹ˆ‡”‹‘”‹–›‹ ‘—–‡”ƒ –‹‰Š‡ƒ”–ˆƒ‹Ž—”‡Šƒ• „‡‡•—‰‰‡•–‡†‹•‘‡•–—†‹‡•ʹͲ͸Ǥ

‡•‹†‡•‡†‹ ƒ–‹‘ǡŽ‹ˆ‡•–›Ž‡ Šƒ‰‡••— Šƒ• ‡••ƒ–‹‘‘ˆ•‘‹‰ǡ”‡†— –‹‘‘ˆ•ƒŽ– ‹–ƒ‡ƒ†ƒŽ ‘Š‘Ž ‘•—’–‹‘ǡ™‡‹‰Š–Ž‘••ƒ•™‡ŽŽƒ•‹ ”‡ƒ•‡‹’Š›•‹ ƒŽƒ –‹˜‹–›ƒ”‡ ”— ‹ƒŽ‹–Š‡–”‡ƒ–‡–‘”’”‡˜‡–‹‘‘ˆŠ›’‡”–‡•‹‘ƒ†ƒ›”‡†— ‡–Š‡”‹•ˆ‘”•‡ Ǧ ‘†ƒ”› ‘’Ž‹ ƒ–‹‘•ʹͲ͸Ǥ

6.3.2 Primary hyperaldosteronism ”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ȋ ȌǡƒŽ•‘”‡ˆ‡””‡†–‘ƒ•’”‹ƒ”›ƒŽ†‘•–‡”‘‹•ǡ‹•ƒ ‹’‘”–ƒ–ˆ‘”‘ˆ•‡ ‘†ƒ”›Š›’‡”–‡•‹‘ƒ†ƒˆˆ‡ –•ƒ”‘—†͸ǦͳͳΨ‘ˆ’ƒ–‹‡–•‹Š›Ǧ ’‡”–‡•‹‘”‡ˆ‡””ƒŽ ‡–‡”•Ǧ‹–•’”‡˜ƒŽ‡ ‡‹ ”‡ƒ•‹‰‹’ƒ–‹‡–‰”‘—’•™‹–ŠŠ‹‰Š‡” „Ž‘‘†’”‡••—”‡ʹ͵ͳȂʹ͵͵Ǥ”‡˜ƒŽ‡ ‡‘ˆ ƒ‘‰Š›’‡”–‡•‹˜‡’ƒ–‹‡–•‹’”‹ƒ”› ƒ”‡ ’”ƒ –‹ ‡•‹••—‰‰‡•–‡†–‘„‡̱ͶǦ͸Ψʹ͵ͳǡʹ͵ͶǤ ‹• Šƒ”ƒ –‡”‹œ‡†„›ƒƒŽ†‘•–‡”‘‡’”‘Ǧ †— –‹‘–Šƒ–„‡ ‘‡•”‡Žƒ–‹˜‡Ž›‹†‡’‡†‡–‘ˆ–Š‡‘”ƒŽ’Š›•‹‘Ž‘‰‹ ƒŽ•–‹—Ž‹ǡ™Š‹ Š

ʹͺ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ Ž‡ƒ†•–‘Š‹‰Š•‡”—ƒŽ†‘•–‡”‘‡ƒ†•—’’”‡••‡†’Žƒ•ƒ”‡‹ǡ‹ ”‡ƒ•‡†™ƒ–‡”ƒ† ƒΪ”‡–‡–‹‘ƒ•™‡ŽŽƒ•‹ ”‡ƒ•‡†’‘–ƒ••‹—‡š ”‡–‹‘ǤŠ‡Žƒ––‡”‡ˆˆ‡ –ǡ‹ˆ•‡˜‡”‡ƒ† —–”‡ƒ–‡†ˆ‘”ƒ’”‘Ž‘‰‡†ƒ‘—–‘ˆ–‹‡ǡ ƒŽ‡ƒ†–‘Š›’‘ƒŽ‡‹ƒ‹•‘‡’ƒ–‹‡–•ʹ͵ͳǤ

‡‹’‘”–ƒ–˜ƒŽ—‡ˆ‘”–Š‡†‹ƒ‰‘•‹•‘ˆ ‹•–Š‡ƒŽ†‘•–‡”‘‡Ǧ–‘Ǧ”‡‹”ƒ–‹‘ȋȌǤ Š‡‡ƒ•—”‡†‹–Š‡‘”‹‰‹•‡ƒ–‡†’ƒ–‹‡–•ǡ ‘‘ —–‘ˆˆ˜ƒŽ—‡•ƒ”‡‹ „‡–™‡‡ʹͲǦͶͲ‰Ȁ†Ž’‡”‰ȀȀŠǤ ‘”’ƒ–‹‡–•™‹–Šƒƒ„‘˜‡–Šƒ–”ƒ‰‡ ‘Ǧ ˆ‹”ƒ–‘”›–‡•–‹‰‹•”‡ ‘‡†‡†ˆ‘” ‘ Ž—•‹˜‡†‹ƒ‰‘•‹•‘ˆ Ǥ ‘™‡˜‡”ǡ‹– ƒ„‡ ‘‹––‡†‹•—„Œ‡ –•’”‡•‡–‹‰™‹–Š•‡˜‡”‡•‹‰•‹†‹ ƒ–‹‰ ʹ͵ͳǤ

‹†‡Ž›ƒ ‡’–‡†–‡•–‹‰’”‘ ‡†—”‡•ƒ”‡ˆŽ—†”‘ ‘”–‹•‘‡•—’’”‡••‹‘ǡ‘”ƒŽ•‘†‹—Ž‘ƒ†Ǧ ‹‰ǡ•ƒŽ‹‡‹ˆ—•‹‘ǡ‘” ƒ’–‘’”‹Ž ŠƒŽŽ‡‰‡ʹ͵ͳǤ ‰‡‡”ƒŽǡ–Š‡•‡–‡•–•ƒ”‡†‡•‹‰‡†–‘†‹•Ǧ Ž‘•‡ƒ—–‘‘‘—•ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǤŠ‡›‡š’‘•‡–Š‡’ƒ–‹‡––‘ ‘†‹–‹‘•–Šƒ– ™‘—Ž†‘”ƒŽŽ› ƒ—•‡ƒŽ†‘•–‡”‘‡•—’’”‡••‹‘„›–Š‡Ǥ ˆƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•”‡Ǧ ƒ‹‡Ž‡˜ƒ–‡††‡•’‹–‡–Š‡•‡ ‘†‹–‹‘•ǡ ‹•ƒŽ‹‡Ž›†‹ƒ‰‘•‹•ʹ͵ͷǤ ‘”‡šƒ’Ž‡ǡ–Š‡ •ƒŽ‹‡‹ˆ—•‹‘–‡•–ƒ••‡•ƒŽ†‘•–‡”‘‡•—’’”‡••‹‘„›‹ ”‡ƒ•‡†„Ž‘‘†˜‘Ž—‡ƒ†ƒΪ ”‡–‡–‹‘ʹ͵ͷǣŠ‡’ƒ–‹‡–‹•‹ˆ—•‡†™‹–Š—•—ƒŽŽ›ʹŽ‹–‡”•‘ˆͲǤͻΨ•ƒŽ‹‡‘˜‡”ͶŠ‘—”• ˆ‘ŽŽ‘™‡†„›ƒ‡ƒ•—”‡‡–‘ˆ’Žƒ•ƒƒŽ†‘•–‡”‘‡ʹ͵ͳǤ

Š‡‘•– ‘‘ ƒ—•‡‘ˆ ‹•„‹Žƒ–‡”ƒŽ‹†‹‘’ƒ–Š‹ Š›’‡”’Žƒ•‹ƒ‘ˆ–Š‡ƒ†”‡ƒŽ‰Žƒ†ǡ ƒˆˆ‡ –‹‰ƒ”‘—†͸ͲΨ‘ˆ’ƒ–‹‡–•ˆ‘ŽŽ‘™‡†„›ƒ†”‡ƒŽƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒǡ ƒ‹‰—’ƒ’’”‘š‹ƒ–‡Ž›‘‡–Š‹”†‘ˆ  ƒ•‡•Ǥ „‹Žƒ–‡”ƒŽƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ„‘–Š ƒ†”‡ƒŽ• ‘–”‹„—–‡–‘–Š‡‹ ”‡ƒ•‡‹ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǡ™Š‹ Š‹‰Š–‹˜‘Ž˜‡‹Ǧ ”‘Ǧ‘”ƒ ”‘‘†—Žƒ”‡Žƒ”‰‡‡–‘ˆ„‘–Šƒ†”‡ƒŽ‰Žƒ†•ʹ͵͸ǤŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ƒ†‡‘ƒ•ƒ”‡„‡‹‰–—‘”•‘ˆ–Š‡ƒ†”‡ƒŽ‰Žƒ†ƒ”‡†„›•—•–ƒ‹‡†ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘‹†‡’‡†‡–‘ˆ”‡‰—Žƒ–‹‘„›–Š‡ʹ͵͹ǤŠ‡‹”•—„ˆ‘”•ƒ†—†‡”Ž›‹‰ ‡ Šƒ‹••™‹ŽŽ„‡‡Ž— ‹†ƒ–‡†‹•‡ –‹‘͸Ǥ͵ǤʹǤͳǤ‹Žƒ–‡”ƒŽŠ›’‡”’Žƒ•‹ƒȋ̱ʹΨȌǡ‹˜‘Ž˜Ǧ ‹‰‡Žƒ”‰‡‡–‘ˆ‘‡ƒ†”‡ƒŽ‰Žƒ†ǡƒ†”‡ƒŽƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒȋδͳΨȌƒ•™‡ŽŽƒ•‡ –‘’‹ ƒŽ†‘•–‡”‘‡’”‘†— ‹‰ƒ†‡‘ƒƒ† ƒ” ‹‘ƒ ȋδͲǤͳΨȌǡ Š‘”‘‡Ǧ’”‘†— ‹‰ –—‘”• Ž‘ ƒ–‡† ‘—–•‹†‡ –Š‡ ƒ†”‡ƒŽ ‰Žƒ†ǡ ƒ”‡ ˜‡”› ”ƒ”‡ʹ͵͸ǡʹ͵ͺǤ‡’‘”–•‘–Š‡‘ —””‡ ‡‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•ƒ‘‰ ’ƒǦ –‹‡–•˜ƒ”›ǣ‡ ‡–•–—†‹‡•ˆ”‘ ‡”ƒ›ƒ† –ƒŽ›•—‰‰‡•–ƒ’”‡˜ƒŽ‡ ‡ˆ”‘ͳΨ–‘ ‘˜‡”͸Ψȋ ‘’ƒ”‡ʹ͵ͻȂʹͶͳȌǤ

‘–‡•–™Š‹ Š•—„–›’‡‘ˆ ƒ’ƒ–‹‡–’”‡•‡–•™‹–Šǡƒ• ƒ‹•”‡ ‘‡†‡†ƒ•ƒ ˆ‹”•–•–‡’Ǥ ƒ‰‹‰–‡ Š‹“—‡•ƒ”‡Š‡Ž’ˆ—Ž–‘†‡–‡ –Žƒ”‰‡ƒ••‡•ǡ•— Šƒ•ƒ†”‡ƒŽ ƒ” ‹Ǧ

ʹͻ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‘ƒǤ ‘™‡˜‡”ǡ–Š‡›•‡‡‹•—ˆˆ‹ ‹‡–‹–Š‡†‡–‡ –‹‘‘ˆƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡Ǧ ‘ƒǡ™Š‹ Š‹‰Š–„‡Šƒ”†–‘†‹•–‹‰—‹•Šˆ”‘Š›’‡”’Žƒ•‹ƒƒ† ƒ‘–„‡†‹ˆˆ‡”‡–‹Ǧ ƒ–‡†ˆ”‘‘Ǧˆ— –‹‘‹‰ƒ†‡‘ƒ‘” ƒ„‡•ƒŽŽʹ͵ͳǤ

‹ ‡ƒ”‡Ž‹ƒ„Ž‡†‹ƒ‰‘•‹•‘ˆŽƒ–‡”ƒŽ‹œƒ–‹‘ ƒ‘–„‡ƒ Š‹‡˜‡†˜‹ƒ‹ƒ‰‹‰–‡ Š‹“—‡•ǡ „‹Žƒ–‡”ƒŽƒ†”‡ƒŽ˜‡‹•ƒ’Ž‹‰ȋȌ‹•”‡ ‘‡†‡†ˆ‘”–Š‹•’—”’‘•‡Ǥ –Š‹•’”‘ ‡Ǧ †—”‡ǡ–Š‡”‹‰Š–ƒ†Ž‡ˆ–ƒ†”‡ƒŽ˜‡‹ƒ”‡ ƒ–Š‡–‡”‹œ‡†ʹ͵ͳǤŠ‡’Žƒ•ƒƒŽ†‘•–‡”‘‡ ‘Ǧ ‡–”ƒ–‹‘ȋȌ‹•†‡–‡”‹‡†‹–Š‡ƒ†”‡ƒŽ˜‡‹„Ž‘‘†•ƒ’Ž‡•ƒ†–Š‡ ‘”–‹•‘ŽǦ ‘”Ǧ ”‡ –‡†Žƒ–‡”ƒŽ‹œƒ–‹‘‹†‡š‹•†‡–‡”‹‡†Ǥ ‘”’”‘ ‡†—”‡•’‡”ˆ‘”‡†™‹–Š‘—– ‘•›–”‘Ǧ ’‹ȋ•›–Š‡–‹  ͳǦʹͶȌ•–‹—Žƒ–‹‘ǡƒ‹†‡š‘ˆʹǣͳ‹•‰‡‡”ƒŽŽ› ‘•‹†‡”‡†’‘•‹–‹˜‡ ˆ‘”Žƒ–‡”ƒŽ‹œƒ–‹‘ʹ͵ͳǡʹͶʹǤ‡•’‹–‡‹–•„‡‡ˆ‹–•ǡƒ†”‡ƒŽ˜‡‹•ƒ’Ž‹‰‹•ƒ ‘•–Ž›ƒ•™‡ŽŽƒ• ‹˜ƒ•‹˜‡’”‘ ‡†—”‡ƒ†”‡“—‹”‡•ƒ•‹ŽŽ‡†’”ƒ –‹–‹‘‡”ǤŠ‡”‡ˆ‘”‡ǡ‹–‹•‘– ‘•‹•–‡–Ž› —•‡†‹”‡ˆ‡””ƒŽ ‡–‡”•ʹ͵ͳǡʹͶ͵Ǥ

6.3.2.1 Aldosterone-producing adenoma ƒ†”‡ƒŽƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ƒ†‡‘ƒ•ȋ•Ȍ ‘•–‹–—–‹˜‡ƒŽ†‘•–‡”‘‡’”‘†— Ǧ –‹‘ǡ™Š‹ Š ƒ ƒ—•‡ ǡŠƒ•„‡‡–”ƒ ‡†„ƒ –‘ƒ˜ƒ”‹‡–›‘ˆ‰‡‡–‹ ƒŽ–‡”ƒ–‹‘•‹ –Š‡ –—‘”‹‰‡‹  –‹••—‡Ǥ ‡‡–‹  ƒƒŽ›•‹• ‘ˆ • •Š‘™‡† •‘ƒ–‹ —–ƒ–‹‘•‹–Š‡ ‰‡‡•KCNJ5ǡCACNA1DǡATP1A1ǡATP2B3ƒ†CTNNB1ͳʹͳǡͳͻ͹ǡʹͶͶǡʹͶͷǤ

Š‹•™‘”‹ Ž—†‡•ƒ•–—†›™Š‹ Š‹˜‡•–‹‰ƒ–‡•–Š‡—–ƒ–‹‘ƒŽ•–ƒ–—•‘ˆ• ‘•‹†‡”Ǧ ‹‰ Ž‹‹ ƒŽ’Š‡‘–›’‡‘ˆ–Š‡’ƒ–‹‡–•ǡƒ•™‡ŽŽƒ•Š‹•–‘Ž‘‰‹ ƒŽ Šƒ”ƒ –‡”‹•–‹ •‘ˆ–Š‡–—Ǧ ‘”Ǥ‡š–‡•‹˜‡‘˜‡”˜‹‡™‘ˆ’”‡˜‹‘—•”‡’‘”–•‘—–ƒ–‹‘•ƒ†–Š‡‹”†‹•–‹ –‹˜‡ ˆ‡ƒ–—”‡• ƒ „‡ ˆ‘—† ‹ ƒ„Ž‡ ͸ǡ ƒ„Ž‡ ͹ǡ ƒ„Ž‡ ͺ ƒ† ƒ„Ž‡ ͻ ‹–Š‡ƒ’’‡†‹š ȋ•‡ –‹‘ͳͳǤͷȌǤ

6.3.2.1.1KCNJ5 mutations in aldosterone-producing adenomas KCNJ5—–ƒ–‹‘•ƒ”‡˜‡”› ‘‘Ǣ–Š‡›ƒ”‡ˆ‘—†‹ƒ”‘—†ͶͲΨ‘ˆ•ƒŽ–Š‘—‰Š‹– Šƒ•„‡‡•—‰‰‡•–‡†–Šƒ––Š‡’‡” ‡–ƒ‰‡‘ˆ•™‹–ŠKCNJ5 —–ƒ–‹‘•‹•Ž‘™‡”™Š‡ Ž‡•••–”‹‰‡–†‹ƒ‰‘•‹• ”‹–‡”‹ƒˆ‘”Žƒ–‡”ƒŽ‹œƒ–‹‘ƒ”‡ƒ’’Ž‹‡†ʹ͵͹ǡʹͶ͸ǡʹͶ͹ȋƒ„Ž‡ͳƒ†ƒǦ „Ž‡ʹȌǤ’ƒ–‹‡–•™‹–ŠKCNJ5 —–ƒ–‹‘•–‡†–‘„‡›‘—‰‡”–Šƒ–Š‘•‡™‹–Š‘—––Š‡•‡ —–ƒ–‹‘•ȋ ‘’ƒ”‡‡Ǥ‰ǤͳͻͺǡʹͶ͸ǡʹͶͺǡʹͶͻƒ†ƒ„Ž‡ʹȌǤ–—†‹‡•†‘‡‹—”‘’‡ƒ‘”—•Ǧ –”ƒŽ‹ƒ ‡–‡”•‘ˆ–‡”‡’‘”–KCNJ5—–ƒ–‹‘•–‘„‡‘”‡ˆ”‡“—‡–‹™‘‡–Šƒ‹ ‡ȋ ‘’ƒ”‡‡Ǥ‰Ǥͳͷ͹ǡʹͶ͸ǡʹͷͲǡʹͷͳƒ†ƒ„Ž‡ʹȌǤ –Šƒ•„‡‡ƒ”‰—‡†–Šƒ––Š‹•„‹ƒ•ƒ’’‡ƒ”• –‘„‡Ž‡••’”‘‘— ‡†‹ƒ•–•‹ƒͳͷ͹ǡʹͶͺǡʹͷʹǤ ‘™‡˜‡”ǡ•‡˜‡”ƒŽ•–—†‹‡•ˆ”‘–Š‡”‡‰‹‘ •–‹ŽŽ”‡’‘”–ˆ‡ƒŽ‡’”‡†‘‹ƒ ‡ȋ ‘’ƒ”‡‡Ǥ‰Ǥͳͻͺǡʹͷ͵ȌǤŽ•‘ǡ’”‡˜ƒŽ‡ ‡‘ˆKCNJ5—Ǧ –ƒ–‹‘•‹•ƒ’’‡ƒ”•–‘„‡Š‹‰Š‡”‹ƒ•–•‹ƒ ‡–‡”•ȋ̱͸ͲǦ͹ͲΨǡƒ„Ž‡ͳȌǡ™Š‹ Š

͵Ͳ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ Šƒ•„‡‡•—‰‰‡•–‡†–‘„‡ƒDz•‡Ž‡ –‹‘„‹ƒ•dz”‡•—Ž–‹‰ˆ”‘†‹ƒ‰‘•–‹  ”‹–‡”‹ƒ•Š‹ˆ–‡† –‘™ƒ”†• ’ƒ–‹‡–• ™‹–Š ƒ ‘”‡ •‡˜‡”‡ ’Š‡‘–›’‡ ƒ† ’”‘ ‡†—”ƒŽ †‹ˆˆ‡”Ǧ ‡ ‡•ͳͷ͹ǡʹͶ͹ǡʹͶͺǡʹͷʹȂʹͷͷǤ•ƒ‘–ƒ„Ž‡‡š ‡’–‹‘ǡƒƒ‹™ƒ‡•‡•–—†›ƒƒŽ›œ‹‰͸ͻ•”‡Ǧ ’‘”–•ƒ’”‡˜ƒŽ‡ ‡‘ˆKCNJ5—–ƒ–‹‘••‹‹Žƒ”–‘—”‘’‡ƒ•–—†‹‡•ȋ͵͹ΨȌͳͻͺǤ‘‡ •–—†‹‡•”‡’‘”–Š‹‰Š‡”’Žƒ•ƒƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•ʹͶ͸ǡʹͶͺƒ•™‡ŽŽƒ•Ž‘™‡”•‡”—’‘–ƒ•Ǧ •‹—Ž‡˜‡Ž•ʹͶͺǡʹͷͲ‹’ƒ–‹‡–•™‹–ŠKCNJ5Ǧ—–ƒ–‡†•ȋƒ„Ž‡ʹȌǤ—‘”•™‹–ŠKCNJ5 —–ƒ–‹‘• ƒ”‡ ‘ˆ–‡ †‡• ”‹„‡† –‘ Šƒ˜‡ ˆƒ• ‹ —Žƒ–ƒǦŽ‹‡ ƒ’’‡ƒ”ƒ ‡ʹͷ͸Ȃʹͷͺ ƒ• ™‡ŽŽ ƒ• Žƒ”‰‡”•‹œ‡ȋ ‘’ƒ”‡‡Ǥ‰ǤͳͻͺǡʹͶͺǡʹͷͳǡʹͷ͵ǡʹͷ͹ǡʹͷͻƒ†ƒ„Ž‡ʹȌǤ‡–ƒǦƒƒŽ›•‹• ‘’”‹•‹‰ ͳ͸͵͸•’ƒ–‹‡–•‹ͳ͵•–—†‹‡• ‘ˆ‹”‡†‡› Šƒ”ƒ –‡”‹•–‹ •‘ˆ–—‘”•™‹–ŠKCNJ5 —–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‘•‡™‹–Š‘—–ǣ›‘—‰‡”ƒ‰‡ǡŽƒ”‰‡”–—‘”•ǡŠ‹‰Š‡”’Žƒ•ƒ ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•ƒ•™‡ŽŽƒ•ˆ‡ƒŽ‡„‹ƒ•ʹͶ͹Ǥ‘”‡‘˜‡”ǡƒ•–—†›„›‹–ƒ‘–‘et al.ˆ‘—† –Šƒ–’ƒ–‹‡–•™‹–ŠKCNJ5-—–ƒ–‡†•†‹•’Žƒ›ƒŠ‹‰Š‡”‹’”‘˜‡‡–‹†‡–‡”‹ƒǦ –‘”•‘ˆ ƒ”†‹‘˜ƒ• —Žƒ””‹•ƒˆ–‡”ƒ†”‡ƒŽ‡ –‘›–Šƒ’ƒ–‹‡–•™‹–Š –—‘”• ™‹–Š‘—– ‘™—–ƒ–‹‘•ʹͶͺǤ

‘ƒ–‹ KCNJ5—–ƒ–‹‘•‹•ƒ”‡—•—ƒŽŽ›ƒ ‘’ƒ‹‡†„›‘Ž›ƒˆ‡™ƒ††‹–‹‘ƒŽ —–ƒ–‹‘•Ǥ™‘KCNJ5—–ƒ–‹‘•ǡƒ‡Ž›G151Rƒ†L168Rǡƒ ‘—–ˆ‘”‘•–‘ˆ–Š‡ ƒ•‡•Ǣ‘–Š‡”—–ƒ–‹‘•‹KCNJ5ƒ”‡”ƒ”‡ͳͻ͹ǡʹ͵͹ȋƒ„Ž‡ʹȌǤ‘–Š–Š‡ ͳͷͳƒ†ͳ͸ͺ ˜ƒ”‹ƒ–ƒ”‡Ž‘ ƒ–‡†‹‘”‹˜‹ ‹‹–›–‘–Š‡•‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”ǡŽ‡ƒ†‹‰–‘ƒŽ‘••‘ˆ•‡Ž‡ –‹˜‹–› ƒ†ƒŽŽ‘™‹‰ˆ‘”ƒΪ‹ˆŽ—š‹–‘–Š‡ ‡ŽŽǤŠ‡’ƒ–Š‘‡ Šƒ‹••—‰‰‡•–‡†‹•–Šƒ––Š‹•ƒΪ ‹ˆŽ—š Ž‡ƒ†• –‘ †‡’‘Žƒ”‹œƒ–‹‘ ‘ˆ –Š‡ ‡ŽŽ ‡„”ƒ‡ǡ ƒ—•‹‰ ˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•–‘‘’‡ǡ–Š‡”‡„›‹ ”‡ƒ•‹‰‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•ǤŠ‹••–‹—Žƒ–‡• ‡ŽŽ’”‘Ǧ Ž‹ˆ‡”ƒ–‹‘ƒ•™‡ŽŽƒ•ƒŽ†‘•–‡”‘‡•›–Š‡•‹•–Š”‘—‰Š‹ ”‡ƒ•‡†‡š’”‡••‹‘‘ˆCYP11B2ͳͻ͹ ȋ ‹‰—”‡ͷȌǤ‡ŽŽ†‡’‘Žƒ”‹œƒ–‹‘ƒ†ƒΪ ‘†— –ƒ ‡‘ˆ—–ƒ– Šƒ‡Ž•™‡”‡‹‹–‹ƒŽŽ› •Š‘™‹‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡•‹  ‡ŽŽ•ǤIn vitro•–—†‹‡•‹ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡•ˆ—”–Š‡” ‘ˆ‹”–Š‡†‹ˆˆ‡”‡–ƒ•’‡ –•‘ˆ–Š‹•‡ Šƒ‹•ǣƒ—„‡”et al.†‡• ”‹„‡†‘”‡†‡’‘Žƒ”‹œ‡†‡„”ƒ‡’‘–‡–‹ƒŽ•‹ ʹͻͷ ‡ŽŽ•™‹–Š–Š‡L168R —–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡Ǥ‘”‡‘˜‡”ǡ–Š‡G151Rƒ†L168R—–ƒ–‹‘• Ž‡ƒ†–‘‡Ž‡˜ƒ–‡†‹–”ƒ ‡ŽŽ—Žƒ”ƒΪƒ†ƒʹΪ ‘ ‡–”ƒ–‹‘•‹–Š‡•‡ ‡ŽŽ•ʹͲ͵ǤŠ‡‡ˆˆ‡ –‘ˆ  ͷ ͳͷͳƒ†ͳ͸ͺ ‹ ”‡ƒ•‹‰CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ Šƒ•„‡‡ ‘ˆ‹”‡†‹ ‡ŽŽ —Ž–—”‡•–—†‹‡•—•‹‰–Š‡ ‡ŽŽŽ‹‡ ͳͷʹͷͲǤ

Ž–Š‘—‰Š–Š‡”‡‹•ƒ‰‡‡”ƒŽ ‘•‡•—•–Šƒ–CYP11B2ƒ†KCNJ5ƒ”‡‡š’”‡••‡†‹• ™‹–Š—–ƒ–‹‘•‹–Š‡Žƒ––‡”‰‡‡ǡ–Š‡”‡ƒ”‡ ‘ˆŽ‹ –‹‰”‡’‘”–•ƒ„‘—–Ž‡˜‡Ž•‘ˆ‡š’”‡•Ǧ •‹‘‹ ‘’ƒ”‹•‘–‘‘–Š‡”•ǣŠ‡”‡ƒ•ƒ‰— Š‹et al.†‡• ”‹„‡‹ ”‡ƒ•‡†Ž‡˜‡Ž•‘ˆ „‘–ŠKCNJ5ƒ†’”‘–‡‹‹•™‹–ŠKCNJ5—–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‘•‡

͵ͳ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ™‹–Š‘—–ʹͷͶǡ‘—Ž”‘—et al.ˆ‘—†‘•‹‰‹ˆ‹ ƒ– ‘””‡Žƒ–‹‘‘ˆKCNJ5Ž‡˜‡Ž•ƒ† —–ƒ–‹‘ƒŽ•–ƒ–—•‘ˆ–Š‡–—‘”•ǡ„—–†‡• ”‹„‡–Š‡”ƒ–‹‘‘ˆ ͷ’”‘–‡‹‹–—‘”‹‰‡‹  –‹••—‡ ‘’ƒ”‡†–‘‘”ƒŽƒ†Œƒ ‡––‹••—‡–‘„‡Ž‘™‡”‹–—‘”• ƒ””›‹‰KCNJ5—–ƒǦ –‹‘•ʹ͸ͲǤŠ‡Žƒ––‡””‡•—Ž–•ƒ”‡ ‘ˆ‹”‡†„›ƒ‘–Š‡”•–—†›ͳͻͺǤ ‘™‡˜‡”ǡ‡”•–”ڏet al.ˆ‘—†‘ ‘””‡Žƒ–‹‘„‡–™‡‡—–ƒ–‹‘ƒŽ•–ƒ–—•ƒ† ͷ’”‘–‡‹‡š’”‡••‹‘‹ –Š‡‹”ʹͲͳʹ•–—†›ʹͷͳǤš’”‡••‹‘‘ˆCYP11B2™ƒ•”‡’‘”–‡†–‘„‡Š‹‰Š‡”‹–—‘”•™‹–Š KCNJ5—–ƒ–‹‘–Šƒ‘–Š‡”•‹•‘‡•–—†‹‡•ǡ™Š‹Ž‡‘–Š‡”•”‡’‘”–‘†‹ˆˆ‡”‡ ‡• ȋ ‘’ƒ”‡ʹͶ͸ǡʹͷͲǡʹ͸ͳǡʹ͸ʹȌǤ‘–Š‡”‰‡‡–Šƒ–™ƒ•ˆ‘—†–‘„‡—’”‡‰—Žƒ–‡†‹•™‹–Š KCNJ5—–ƒ–‹‘•‹ ‘’ƒ”‹•‘–‘–Š‘•‡™‹–Š‘—–‹•VSNL1ǡ™Š‹ Š ‘†‡•ˆ‘”–Š‡‡—Ǧ ”‘ƒŽ ƒŽ ‹—•‡•‘”’”‘–‡‹˜‹•‹‹ǦŽ‹‡ͳǤIn vitro‡š’‡”‹‡–•Šƒ˜‡•Š‘™–Šƒ–‹–• ‘˜‡”‡š’”‡••‹‘ ‹ ”‡ƒ•‡• CYP11B2‡š’”‡••‹‘‹–Š‡ƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ʹͻͷƒ†ƒ’’‡ƒ”•–‘ƒŽ•‘”‡†— ‡ƒʹΪǦ‡†‹ƒ–‡†ƒ’‘’–‘•‹•‹–Š‡•‡ ‡ŽŽ•ʹ͸ͳǤ

—–ƒ– ͷ Šƒ‡Ž•‰‡‡”ƒŽŽ›•Š‘™ƒŽ–‡”‡†’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ“—ƒŽ‹–‹‡•‹ ‘’ƒ”‹Ǧ •‘–‘–Š‡™‹Ž†–›’‡ǣŠ‡‹” Šƒ‡Ž„Ž‘ ‡”–‡”–‹ƒ’‹ȋͳ͸ͺȌƒ•™‡ŽŽƒ•–Š‡’‘–ƒ•Ǧ •‹— Šƒ‡Ž„Ž‘ ‡”ƒʹΪȋ ͳͷͳǡͳ͸ͺȌŠƒ”†Ž›ƒˆˆ‡ –—–ƒ– Šƒ‡Ž•ͳͻ͹ǡʹͲ͵Ǥƒ—„‡” et al.‹†‡–‹ˆ‹‡†–Š‡ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡”˜‡”ƒ’ƒ‹Žƒ•ƒ‹Š‹„‹–‘”‘ˆ ͷͳ͸ͺ ƒ– ‘ ‡–”ƒ–‹‘•–Šƒ–ƒ”‡‹–Š‡”ƒ‰‡‘ˆƒ––ƒ‹ƒ„Ž‡„Ž‘‘†’Žƒ•ƒŽ‡˜‡Ž•Ǥ‘”‡‘˜‡”ǡ ‘–Š‡” „Ž‘ ‡”• ‘ˆ ƒʹΪǦ ƒ† ƒΪǦ ‘†— –‹‰’”‘–‡‹•ǡ ƒ‘‰ –Š‡ –Š‡ †‹—”‡–‹  ƒ‹Ǧ Ž‘”‹†‡ǡ•‡‡–‘ƒ –ƒ•‹Š‹„‹–‘”•‘ˆ ͷͳ͸ͺ Šƒ‡Ž•ǡ™Š‹Ž‡•‘‡‹‰Š–ƒŽ•‘ƒˆˆ‡ – –Š‡™‹Ž†–›’‡ʹͲ͵Ǥ‹ ‡KCNJ5—–ƒ–‹‘•ƒ ‘—–ˆ‘”ƒŠ‹‰Š’‡” ‡–ƒ‰‡‘ˆ•ǡˆ‹†‹‰ ’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ‹Š‹„‹–‘”•‘ˆ–Š‡•‡ Šƒ‡Ž•‹‰Š–„‡„‡‡ˆ‹ ‹ƒŽ‹–Š‡–”‡ƒ–‡–‘ˆ ƒˆˆ‡ –‡†’ƒ–‹‡–•ǤŠ‡›‹‰Š–ƒŽ•‘ ‘—–‡”ƒ ––—‘”’”‘‰”‡••‹‘„›‹Š‹„‹–‹‰’”‘Ž‹ˆ‡”Ǧ ƒ–‹‘‡†‹ƒ–‡†„›—–ƒ– ͷ Šƒ‡Ž•ǤŠ‹Ž‡‘”ƒŽŽ› ‘•‹†‡”‡†–‘Šƒ˜‡‡ˆˆ‡ –• ‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘–Šƒ–ƒ”‡‡‰Ž‹‰‹„Ž‡†—”‹‰‹†‹ ƒ–‹˜‡–‡•–‹‰ǡ˜‡”ƒ’ƒ‹Žƒ†Ǧ ‹‹•–‡”‡†‹Š‹‰Š†‘•‡•ȋ͵šͳʹͲ‰Ȁ†Ȍ‹‰Š–Šƒ’‡”–Š‡†‹ƒ‰‘•‹•‘ˆ ‹•‘‡ ’ƒ–‹‡–•„›ƒˆˆ‡ –‹‰–Š‡‹„Ž‘‘†–‡•–•†—‡–‘‹–•‡ˆˆ‡ –‘ ͷͳ͸ͺʹͲ͵ǡʹ͵ͳǤ Ǧ Š‹„‹–‹‘‘ˆKCNJ5 ™‹Ž†–›’‡‹‰Š–ƒŽ•‘‡Ž‹ ‹–—†‡•‹”‡†‡ˆˆ‡ –•ǡ•‹ ‡ƒŽ‘••Ǧ‘ˆǦˆ— –‹‘ —–ƒ–‹‘‹–Š‡‰‡‡Šƒ•„‡‡ƒ••‘ ‹ƒ–‡†™‹–ŠŽ‘‰•›†”‘‡ǡ•–”‡••‹‰–Š‡‹Ǧ ’‘”–ƒ ‡‘ˆ†”—‰•’‡ ‹ˆ‹ ‹–›ͳͻ͸Ǥ‡š–‡•‹˜‡’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ•–—†›‘ˆ—–ƒ– ͷ Šƒ‡Ž•‹•‹ Ž—†‡†‹–Š‹•™‘”Ǥ

––‡’–•ƒ– in vivo‹˜‡•–‹‰ƒ–‹‘•‘ˆKCNJ5—–ƒ–‹‘•ˆ‘—†‹•Šƒ˜‡„‡‡‘ˆŽ‹Ǧ ‹–‡†•— ‡••ǣŠƒ”ƒ –‡”‹•–‹ •‘ˆƒ‘—•‡‘†‡ŽŠƒ”„‘”‹‰–Š‡Š—ƒKCNJ5 G151Rƒ† L168R—–ƒ–‹‘•†‹†‘–”‡’Ž‹ ƒ–‡–Š‡Š—ƒ’Š‡‘–›’‡ʹ͸͵Ǥ‘–ƒ„Ž›ǡKCNJ5‹•‡‹–Š‡”

͵ʹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‡š’”‡••‡†‹–Š‡—”‹‡‘”‹–Š‡”ƒ–ƒ†”‡ƒŽ‰Žƒ†ʹ͸Ͷǡʹ͸ͷǤ Š‹• ‘•–‹–—–‡• ƒ ‹Ǧ ’‘”–ƒ–Ž‹‹–ƒ–‹‘ˆ‘”•–—†‹‡•‹˜‡•–‹‰ƒ–‹‰–Š‡”‘Ž‡‘ˆ—–ƒ– KCNJ5‹ ƒ† •–”‡••‡•–Š‡‹’‘”–ƒ ‡‘ˆin vitro•–—†‹‡•‘”ǡ™Š‡”‡˜‡”ƒ’’Ž‹ ƒ„Ž‡ǡ•–—†‹‡•‘Š—ƒ –‡•–•—„Œ‡ –•ˆ‘”–Š‹•’—”’‘•‡Ǥ

6.3.2.1.2CACNA1D mutations in aldosterone-producing adenomas ‘ƒ–‹ —–ƒ–‹‘•‹CACNA1DŠƒ˜‡ƒŽ•‘„‡‡”‡’‡ƒ–‡†Ž›ˆ‘—†‹•ǡ™‹–Šƒ’”‡˜Ǧ ƒŽ‡ ‡‘ˆ̱ͻǤ͵Ψ”‡’‘”–‡†‹–Š‡•‘ˆƒ”Žƒ”‰‡•–—”‘’‡ƒ ‘Š‘”–ȋ ‘’ƒ”‡ʹ͸ʹƒ†ƒ„Ž‡ ͳȌǤŽ‘™‡”’‡” ‡–ƒ‰‡‘ˆCACNA1D—–ƒ–‹‘•Šƒ•„‡‡†‡• ”‹„‡†‹•‹ƒ ‘Š‘”–• ȋ̱ʹΨǡ ‘’ƒ”‡‡Ǥ‰ǤʹͶͺƒ†ƒ„Ž‡ͳȌǤˆ‘–‡ǡ•‘‡•–—†‹‡•Šƒ˜‡‘–†‡–‡ –‡†—–ƒ–‹‘• ‹CACNA1Dƒ–ƒŽŽȋ ‘’ƒ”‡ʹ͸͸ǡʹ͸͹ƒ†ƒ„Ž‡ͳȌǤ –•Š‘—Ž†„‡‘–‡†ǡ–Šƒ–‘•–•–—†‹‡• ‹˜‡•–‹‰ƒ–‡‘Ž›—–ƒ–‹‘Š‘–•’‘–•ǡƒŽ–Š‘—‰Š‘–ƒŽŽ•’‡ ‹ˆ›–Š‡‹”ƒ’’”‘ƒ Šȋ ‘’ƒ”‡ ‡Ǥ‰Ǥ ʹ͸͸ǡʹ͸͹ȌǤ ‹ ‡ CACNA1D—–ƒ–‹‘•‹•Šƒ˜‡„‡‡‹†‡–‹ˆ‹‡†–Š”‘—‰Š‘—––Š‡ ‰‡‡ǡ‹–‹•’‘••‹„Ž‡–Šƒ–—–ƒ–‹‘•™‡”‡‘˜‡”Ž‘‘‡†‹–Š‡’”‘ ‡••ȋƒŽ•‘ ‘’ƒ”‡ ʹ͸ͺ ƒ† •‡ –‹‘ ͺǤͳǤͳȌǤ •’‡ ‹ƒŽŽ› ™Š‡ ‰”‘—’‡† ™‹–Š ƒ•‡ —–ƒ–‹‘•ǡ CACNA1DǦ—Ǧ –ƒ–‡†•Šƒ˜‡„‡‡†‡• ”‹„‡†–‘„‡•ƒŽŽ‡”ƒ†’ƒ–‹‡–•–‡†–‘„‡‘Ž†‡”‹ ‘’ƒ”Ǧ ‹•‘–‘•™‹–ŠKCNJ5˜ƒ”‹ƒ–•Ǥ ƒ††‹–‹‘ǡ–Š‡”‡ƒ’’‡ƒ”•–‘„‡‘ˆ‡ƒŽ‡„‹ƒ•ȋ ‘Ǧ ’ƒ”‡ͳʹͳǡʹͶͻǡʹͷ͹ǡʹ͸ʹƒ†ƒ„Ž‡ʹȌǤ–ƒ–‡‡–•‘–Š‡Š‹•–‘Ž‘‰‹ ƒŽƒ’’‡ƒ”ƒ ‡‘ˆ–Š‹• ‰”‘—’Šƒ˜‡„‡‡ ‘–”ƒ†‹ –‘”›•‘ˆƒ”ȋ‡Ǥ‰Ǥʹͷͷǡʹ͸ʹǡʹ͸ͻȌǤ

‹‹Žƒ”–‘•™‹–ŠKCNJ5—–ƒ–‹‘•ǡˆ‡™ƒ††‹–‹‘ƒŽ’”‘–‡‹ǦƒŽ–‡”‹‰•‘ƒ–‹ —–ƒǦ –‹‘•‹‘–Š‡”‰‡‡•™‡”‡ˆ‘—†‹–Š‡†‹• ‘˜‡”› ‘Š‘”–ͳʹͳǤ˜ƒ”‹‡–›‘ˆ—–ƒ–‹‘•Šƒ˜‡ „‡‡ˆ‘—†‹†‹ˆˆ‡”‡–ƒ”‡ƒ•‘ˆ–Š‡’”‘–‡‹ǤŠ‡›ˆ”‡“—‡–Ž›ƒˆˆ‡ –•‡‰‡–͸ƒ•™‡ŽŽ ƒ•–Š‡Ž‹‡”„‡–™‡‡•‡‰‡–•Ͷƒ†ͷ‹†‹ˆˆ‡”‡–”‡’‡ƒ–•Ǥ—–ƒ–‹‘•Šƒ˜‡ƒŽ•‘„‡‡ ˆ‘—†‹•‡‰‡–•Ͷƒ†ͷǤŠ‡ƒˆˆŽ‹ –‡†ƒ”‡ƒ•ƒ”‡‹˜‘Ž˜‡†‹–Š‡ˆ‘”‹‰‘ˆ–Š‡ ŠƒǦ ‡Ž’‘”‡ȋ‡Ǥ‰Ǥ ͶͲ͵ǡ ͹ͷͲǡ ͹Ͷ͹ǡ ‘’ƒ”‡ ‹‰—”‡͸Ȍǡ–Š‡˜‘Ž–ƒ‰‡•‡•‘”ȋͻͻͲ Ȍ ‘”–Š‡ͶǦͷŽ‹‡” ‘—’Ž‹‰–Š‡˜‘Ž–ƒ‰‡Ǧ•‡•‘”ƒ†–Š‡’‘”‡ȋ‡Ǥ‰Ǥ ͳ͵͵͸ǡ ʹͷͻȌͳʹͳǡʹ͸ʹǡʹ͸ͻǤŠ‡‘†‡Ž‘ˆ–Š‡’ƒ–Š‘‡ Šƒ‹•ǡ†‡”‹˜‡†ˆ”‘‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ †ƒ–ƒˆ‘”•‘‡‘ˆ–Š‡‘•– ‘‘—–ƒ–‹‘•ǡ”‡Ž‹‡•‘‹ˆŽ—š‘ˆƒʹΪ–Š”‘—‰Šƒ –‹˜ƒ–‹‘ ‘ˆͳ Šƒ‡Ž•ƒ–‘”‡Š›’‡”’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•ƒ†Ȁ‘””‡†— ‡† Šƒ‡Ž‹Ǧ ƒ –‹˜ƒ–‹‘ͳʹͳǡʹ͸ͻȋ ‹‰—”‡ͷȌǤ ʹͻͷ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–ŠCACNA1D P1336Rƒ† V259D•Š‘™ƒ‹ ”‡ƒ•‡‹ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ǡ ™Š‹ Š ƒ„‡”‡†— ‡†™‹–ŠŠ‹‰Š ‘ ‡–”ƒ–‹‘•‘ˆǦ–›’‡ Šƒ‡Ž„Ž‘ ‡”•ʹ͸ͺǤ





͵͵ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ dĂďůĞ ϭ͘ DƵƚĂƚŝŽŶ ĨƌĞƋƵĞŶĐŝĞƐ ŝŶ WƐ ĂĐĐŽƌĚŝŶŐ ƚŽ ĚŝĨĨĞƌĞŶƚ ƐƚƵĚŝĞƐ͘ĚĂƉƚĞĚ ĨƌŽŵ ^ĞŝĚĞů ĂŶĚ ^ĐŚŽůů͕ϮϬϭϲϮϳϬ͘ Study Region Study Mutation frequencies (%) size KCNJ5 CACNA1D ATP1A1 ATP2B3 CTNNB1 ‡”•–”ڏǡʹͲͳʹʹͷͳ ǡ ͵͵ͻ Ͷ͸Ǥ͵ Ȁ Ȁ Ȁ Ȁ ‡”•–”ڏǡ ǡ ͳ͸ͷ ͷͶǤͷ ͵ ͸Ǥͳ ͵ Ȁ ʹͲͳͷƒǡʹͶͻ ‡”•–”ڏǡ ǡ ͳͻͺ Ͷ͸Ǥͷ ͳǤͷ ͵ ͳǤͷ ͷǤͳ ʹͲͳ͸„ǡʹ͹ͳ ”‡•‡ǡʹͲͳ͵ʹ͹ʹ  ʹͺ ͵ͷǤ͹ Ȁ Ȁ Ȁ Ȁ œ‹œƒǡʹͲͳʹʹͷͻ ǡ ͹͵ ͶͳǤͳ Ȁ Ȁ Ȁ Ȁ œ‹œƒǡʹͲͳ͵ ǡʹ͸ͻ  ͳͷʹ Ȁ ͹Ǥͻ ͹Ǥͻ Ȁ Ȁ ‡—• ŠŽ‡‹ǡʹͲͳ͵ʹͶͶ  ͵Ͳͺ ͵ͺǤ͵ Ȁ ͷǤʹ ͳǤ͸ Ȁ ‘—Ž”‘—ǡʹͲͳʹʹͶ͸  ͵ͺͲ ͵͵Ǥͻ Ȁ Ȁ Ȁ Ȁ Š‡‰ǡʹͲͳͷͳͻͺ  ͸ͻ ͵͹Ǥ͹ Ȁ Ȁ Ȁ Ȁ Š‘‹ǡʹͲͳͳͳͻ͹  ʹʹ ͵͸ǤͶ Ȁ Ȁ Ȁ Ȁ ‡‡”•ǡʹͲͳͶʹͷ͸  ͷ͵ ͶͳǤͷ ͳǤͻ ͳǤͻ ͻǤͶ Ȁ —––ƒǡʹͲͳͶʹ͹͵  ͵ͷ ͵ͳǤͶ Ȁ ͷǤ͹ ͺǤ͸ Ȁ ‡”ƒ†‡•Ǧ‘•ƒǡ  Ͷ͹Ͷ ͵ͺ ͻǤ͵ ͷǤ͵ ͳǤ͹ Ȁ ʹͲͳͶʹ͸ʹ ‘‰ǡʹͲͳ͸ʹ͹Ͷ  ͸͸ ͹ͳǤʹ Ͳ Ͳ Ͳ Ȁ ‹–ƒ‘–‘ǡʹͲͳͷʹͶͺ  ͳͲͺ ͸ͻǤͶ ͳǤͻ ʹǤͺ† Ȁ ‹–ƒ‘–‘ǡʹͲͳ͸‡ǡʹͷͷ  ͳͷͻ ͹͵Ǥ͸ ʹǤͷ ͲǤ͸ ʹǤͷ Ȁ —’’—•ƒ›ǡ  ͳͻͷ ʹͶǤ͸ Ͳ ͳǤͷ ͲǤͷ Ȁ ʹͲͳͶʹ͸͸ ‘–‹ ‘‡ǡʹͲͳʹʹͷͲ ǡǡ Ͷ͹ ͵ͺǤ͵ Ȁ Ȁ Ȁ Ȁ  Š‘ŽŽǡʹͲͳ͵ˆǡͳʹͳ ǡ ͸Ͷ ͵ʹǤͺ ͳͲǤͻ ͳǤ͸ ͵Ǥͳ ͵Ǥͳ ƒ†Œ‹‡ǡʹͲͲͻʹͶͷ  ͳͳ Ȁ Ȁ Ȁ Ȁ ͻǤͳ ƒ‰— Š‹ǡʹͲͳʹʹͷͶ  ʹ͵ ͸ͷǤʹ Ȁ Ȁ Ȁ Ȁ ‹ŽŽ‹ƒ•ǡʹͲͳ͵ʹ͹ͷ  ͳͳʹ ͵ͻǤ͵ Ȁ ͸Ǥ͵ ͲǤͻ Ȁ —ǡʹͲͳͷʹ͸͹  ͳͶͺ ͷͻǤͷ Ͳ ͳǤͶ ͲǤ͹ Ȁ —ǡʹͲͳ͹‰ǡʹ͹͸  ʹͳͻ ͷ͵ Ͳ ͳǤͶ ͲǤͷ ͵Ǥ͹ ‡‘—‹ǡʹͲͳʹʹ͹͹  ͳ͸ ͳʹǤͷ Ȁ Ȁ Ȁ Ȁ Š‡‰ǡʹͲͳͷʹͷ͵  ͳ͸ͺ ͹͸Ǥͺ ͲǤ͸ ʹǤͶ ͲǤ͸ Ȁ ǣ—•–”ƒŽ‹ƒǡǣƒ•–•‹ƒǡǣ—”‘’‡ǡǣ‘”–Š‡”‹ ƒǡȀǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ƒ‘˜‡”Žƒ’™‹–Š‡”•–”ڏ et al., ʹͲͳʹƒ†ʹͲͳ͹ǡ„‘˜‡”Žƒ’™‹–Š‡”•–”ڏet al.ǡ ʹͲͳʹƒ†ʹͲͳͷ, ‘˜‡”Žƒ’™‹–Šœ‹œƒet al.ǡʹͲͳʹǡ †ƒ•‡—–ƒ–‹‘ˆ”‡“—‡ ›ǡ•‹ ‡‹†‹˜‹†—ƒŽATP1A1ƒ†ATP2B3—–ƒ–‹‘ˆ”‡“—‡ ‹‡•ƒ”‡‘–ƒ˜ƒ‹ŽƒǦ „Ž‡ǡ‡’‘••‹„Ž‡‘˜‡”Žƒ’™‹–Š‹–ƒ‘–‘et al.ǡʹͲͳͷǡ„—–‘–•’‡ ‹ˆ‹‡†„›ƒ—–Š‘”•ǡˆ‘˜‡”Žƒ’™‹–ŠŠ‘‹et al.ǡ ʹͲͳͳǡ‰Ž‹‡Ž›‘˜‡”Žƒ’™‹–Š—et al.ǡʹͲͳͷǡ„—–‘–•’‡ ‹ˆ‹‡†„›ƒ—–Š‘”•ǡ—„‡”‘ˆCACNA1D—–ƒ–‹‘• ‘ Ž—†‡†ˆ”‘’—„Ž‹ ƒ–‹‘„›’”‘ ‡••‘ˆ‡Ž‹‹ƒ–‹‘

͵Ͷ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ 6.3.2.1.3ATPase mutations in aldosterone-producing adenoma ‡ —””‡–•‘ƒ–‹ —–ƒ–‹‘•‹ATP1A1ǡ ‘†‹‰ˆ‘”–Š‡ƒΪȀΪǦƒ•‡Ƚͳ•—„—‹–ǡƒ† ATP2B3,‡ ‘†‹‰–Š‡’Žƒ•ƒ‡„”ƒ‡ƒʹΪǦƒ•‡͵ǡŠƒ˜‡„‡‡ˆ‘—†‹•ʹͶͶǤ –‘–ƒŽǡƒ•‡—–ƒ–‹‘•Šƒ˜‡„‡‡”‡’‘”–‡†‹ƒ”‘—†̱͸Ψ‘ˆ•™‹–ŠATP1A1 —–ƒ–‹‘•„‡‹‰‰‡‡”ƒŽŽ›‘”‡’”‡˜ƒŽ‡––ŠƒATP2B3—–ƒ–‹‘•ȋ̱ͳǦͷΨ˜•Ǥ̱ͲǤͷǦ ͳǤͷΨǡ”‡•’‡ –‹˜‡Ž›ȋ ‘’ƒ”‡‡Ǥ‰ǤʹͶͶǡʹ͸ʹǡʹ͸͹ǡƒ„Ž‡ͳƒ†ƒ„Ž‡ʹȌǤ‘‡ǡ„—–‘–ƒŽŽǡ•–—†Ǧ ‹‡•”‡’‘”–ƒ‘Ž†‡”ƒ‰‡‘ˆ–Š‡’ƒ–‹‡–•ƒ†ƒŽ‡’”‡†‘‹ƒ ‡‹–—‘”•™‹–Šƒ•‡ —–ƒ–‹‘•ǡ ‡•’‡ ‹ƒŽŽ› ™Š‡ ‰”‘—’‡† ™‹–Š CACNA1DǦ—–ƒ–‡† •ʹͶͶǡʹͶͻǡʹ͸ʹǡʹ͸ͻǡʹ͹͵Ǥ ‘™‡˜‡”ǡ—’‘†‹• ”‹‹ƒ–‹‘„‡–™‡‡ATP1A1ƒ†ATP2B3—–ƒ–‹‘•ǡATP2B3—Ǧ –ƒ–‹‘•‹‰Š–ƒ –—ƒŽŽ›‘ —”‘”‡ˆ”‡“—‡–Ž›‹ˆ‡ƒŽ‡’ƒ–‹‡–•ʹͶǤ‘”‡‘˜‡”ǡƒŠ‹‰Š‡” CYP11B2‡š’”‡••‹‘–Šƒ‹KCNJ5Ǧ—–ƒ–‡†•ƒ†ƒ‰Ž‘‡”—Ž‘•ƒǦŽ‹‡ƒ’’‡ƒ”ƒ ‡ ‘ˆ–Š‡–—‘”Šƒ˜‡„‡‡†‡• ”‹„‡†„›•‘‡ƒ—–Š‘”•„—–‘–„›‘–Š‡”• ȋ ‘’ƒ”‡ ʹͶͻǡʹ͸ʹǡʹ͸ͻǡʹ͹ͷȌǤ ‡‡”ƒŽŽ›ǡͳͳ—–ƒ–‹‘•ƒ”‡‘ˆ–‡ˆ‘—†‹”‡‰‹‘•ƒ••‘ ‹ƒ–‡†™‹–Š‹‘„‹†‹‰Ǥ ͳͲͶǡŽ‘ ƒ–‡†‹–Š‡ͳŠ‡Ž‹š‘ˆ–Š‡’”‘–‡‹ǡ‹•–Š‡‘•–ˆ”‡“—‡–Ž›—–ƒ–‡†ͳͳ ”‡•‹†—‡‹•ǡŽ‡ƒ†‹‰‡‹–Š‡”–‘ƒ‹••‡•‡—–ƒ–‹‘ȋ‰‡‡”ƒŽŽ›ͳͲͶȌ‘”ƒ†‡Ž‡–‹‘ ȋͳͲͲ̴ͳͲͶ†‡Žǡ ‘’ƒ”‡ ‹‰—”‡͸ƒ†ƒ„Ž‡ʹȌǤŠ‹•”‡•‹†—‡‹••—’’‘•‡†–‘‹–‡”ƒ – ™‹–Šƒ‘–Š‡””‡•‹†—‡‹–Š‡ͶŠ‡Ž‹šǡƒ‡Ž›͵͵Ͷǡ–Š—•‡ƒ„Ž‹‰ΪǦ„‹†‹‰ƒ†‘ Ǧ Ž—•‹‘ʹͶͶǡʹͶͻǤ‘–Š‡””‡ —””‡–—–ƒ–‹‘ǡ͵͵ʹ ǡŽ‹‡•‡ƒ”–Š‡Žƒ––‡””‡•‹†—‡ʹͶͶǡʹͶͻǤŠ‡ ͳͲͶ—–ƒ–‹‘Šƒ•„‡‡†‡• ”‹„‡†–‘ ƒ—•‡‘–‘Ž›•‡˜‡”‡†‹•–—”„ƒ ‡‘ˆΪǦ„‹†‹‰ ƒ†ƒ•‡ƒ –‹˜‹–›ǡ„—–ƒŽ•‘ Ϊ‹ˆŽ—š‹–‘–Š‡ ‡ŽŽʹͶͶǡʹ͸ͻǤŠ‡ͳͲͲ̴ͳͲͶ†‡Ž—–ƒ–‹‘ Š‘™‡˜‡”ƒ’’‡ƒ”•–‘ ”‡ƒ–‡‹™ƒ”†ƒΪ —””‡–•ʹ͸ͻǤ”ƒ•ˆ‡ –‹‘‘ˆ—–ƒ–‡†ATP1A1 Ž‡ƒ†•–‘†‡’‘Žƒ”‹œƒ–‹‘ǡƒ•™‡ŽŽƒ•‹ ”‡ƒ•‡†CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘Ǧ †— –‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡‹ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽ•ƒ–„ƒ•ƒŽŽ‡˜‡Žǡ ƒ•™‡ŽŽƒ•ƒˆ–‡”–”‡ƒ–‡–™‹–Š‰ ʹ͸ͻǡʹ͹ͷǡʹ͹ͺȋ ‹‰—”‡ͷȌǤ ‹†‹ˆ‹ ƒ–‹‘‘ˆ–Š‡ ‡ŽŽŠƒ• „‡‡ ‘ˆ‹”‡†‹ ʹͻͷ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–ŠATP1A1 L104Rƒ†V332Gʹ͹ͺǤ

ATP2B3—–ƒ–‹‘•ƒ”‡—•—ƒŽŽ›‹Ǧˆ”ƒ‡†‡Ž‡–‹‘•ƒˆˆ‡ –‹‰–Š‡’‘•‹–‹‘•Ͷʹ͵ǦͶʹͻ‘ˆ–Š‡ ’”‘–‡‹ǡ‹Ǥ‡Ǥ–Š‡ͶŠ‡Ž‹šʹͶͶǡʹͶͻǡʹͷͷǡʹ͸ʹȋ ‹‰—”‡͸ȌǤ –‹•ƒ••—‡†–Šƒ––Š‡•‡—–ƒ–‹‘• ƒ—•‡ ƒŽ–‡”ƒ–‹‘• ‹ ”‡‰‹‘• ‹˜‘Ž˜‡† ‹ ƒʹΪ„‹†‹‰ʹͶǡʹͶͶǤ•–—†›‹™Š‹ Š–Š‡ Ͷʹͷ̴Ͷʹ͸†‡Ž˜ƒ”‹ƒ–™ƒ•‡š’”‡••‡†‹ ʹͻͷ ‡ŽŽ••—‰‰‡•–•ƒΪ ‘†— –ƒ ‡‘ˆ—Ǧ –ƒ–ʹ͵ǡŽ‡ƒ†‹‰–‘‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ǤŠ‡ ‡ŽŽ•‡š’”‡••‹‰–Š‡

͵ͷ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ



&ŝŐƵƌĞϱ͘^ƵŐŐĞƐƚĞĚƉĂƚŚŽŵĞĐŚĂŶŝƐŵƐŽĨŝŽŶĐŚĂŶŶĞůĂŶĚƉƵŵƉŵƵƚĂƚŝŽŶƐŝŵƉůŝĐĂƚĞĚŝŶW,͘Ϳ/ŶƚŚĞ ƵŶƐƚŝŵƵůĂƚĞĚ'ĐĞůů͕ĂĐƚŝǀŝƚLJŽĨEĂнͬ<нͲdWĂƐĞƐ͕ŚĞƌĞƌĞĨĞƌƌĞĚƚŽĂƐdWϭϭĂĨƚĞƌƚŚĞɲͲƐƵďƵŶŝƚŝƐŽĨŽƌŵŝŵͲ ƉůŝĐĂƚĞĚŝŶWƐ͕ĂƐǁĞůůĂƐŽƵƚǁĂƌĚƉŽƚĂƐƐŝƵŵĐƵƌƌĞŶƚƐĐŽŶƚƌŝďƵƚĞƚŽŵĂŝŶƚĂŝŶŝŶŐŵĞŵďƌĂŶĞŚLJƉĞƌƉŽůĂƌŝnjĂͲ ƚŝŽŶ͘sŽůƚĂŐĞͲŐĂƚĞĚĐĂůĐŝƵŵĐŚĂŶŶĞůƐůŝŬĞEϭĂŶĚEϭ,ƌĞŵĂŝŶĐůŽƐĞĚĂŶĚĂϮнͲdWĂƐĞdWϮϯŝƐ ŶĞĂƌůLJŝŶĂĐƚŝǀĞĂƚůŽǁŝŶƚƌĂĐĞůůƵůĂƌĂϮн͘zWϭϭϮĞdžƉƌĞƐƐŝŽŶŝƐƐƵƉƉƌĞƐƐĞĚ͘ͿhƉŽŶďŝŶĚŝŶŐŽĨŶŐ//ƚŽƚŚĞ н н н dϭƌĞĐĞƉƚŽƌŝŶƚŚĞŶŽƌŵĂů'ĐĞůů͕EĂ ͬ< ͲdWĂƐĞĂŶĚŽƵƚǁĂƌĚ< ĐƵƌƌĞŶƚƐĂƌĞďůŽĐŬĞĚ͘ŽǁŶƌĞŐƵůĂƚŝŽŶŽĨ <E:ϱŚĂƐĂůƐŽďĞĞŶĚĞƐĐƌŝďĞĚϮϬϭ͘dŚĞƐĞĂůƚĞƌĂƚŝŽŶƐůĞĂĚƚŽŵĞŵďƌĂŶĞĚĞƉŽůĂƌŝnjĂƚŝŽŶ͕ĐĂƵƐŝŶŐƚŚĞŽƉĞŶŝŶŐ ŽĨǀŽůƚĂŐĞͲŐĂƚĞĚĐĂůĐŝƵŵĐŚĂŶŶĞůƐĂŶĚŝŶĐƌĞĂƐĞĚŝŶƚƌĂĐĞůůƵůĂƌĂϮнůĞǀĞůƐ͕ƐƚŝŵƵůĂƚŝŶŐzWϭϭϮĞdžƉƌĞƐƐŝŽŶ͕ Ϯн ĂŶĚƚŚƵƐĂůĚŽƐƚĞƌŽŶĞƉƌŽĚƵĐƚŝŽŶ͕ĂƐǁĞůůĂƐƉƌŽůŝĨĞƌĂƚŝŽŶ͘;ŽŶƚƌŝďƵƚŝŽŶŽĨ/WϯͲĚĞƉĞŶĚĞŶƚĂ ƌĞůĞĂƐĞĨƌŽŵ ŝŶƚƌĂĐĞůůƵůĂƌƐƉĂĐĞĂŶĚƚŚĞƐƵŐŐĞƐƚĞĚďůŽĐŬĂŐĞŽĨ>ͲƚLJƉĞĂϮнĐŚĂŶŶĞůƐŚĂǀĞďĞĞŶŽŵŝƚƚĞĚŚĞƌĞĨŽƌƐŝŵƉůŝĐŝƚLJ͕ ĨŽƌƌĞǀŝĞǁƐĞĞϮϯͿ͘dWϮϯďĞĐŽŵĞƐĂĐƚŝǀĞĂƚĞůĞǀĂƚĞĚŝŶƚƌĂĐĞůůƵůĂƌĂϮнͲĐŽŶĐĞŶƚƌĂƚŝŽŶƐ͕ƉƌŽŵŽƚŝŶŐĂϮнĐůĞĂƌͲ ĂŶĐĞ͘Ϳ^ŽĚŝƵŵŝŶĨůƵdžƚŚƌŽƵŐŚŵƵƚĂŶƚ<E:ϱĐŚĂŶŶĞůƐůĞĂĚƐƚŽŵĞŵďƌĂŶĞĚĞƉŽůĂƌŝnjĂƚŝŽŶ͕ĂϮнŝŶĨůƵdžƚŚƌŽƵŐŚ ǀŽůƚĂŐĞͲŐĂƚĞĚĐĂůĐŝƵŵĐŚĂŶŶĞůƐĂŶĚƚŚƵƐzWϭϭϮĞdžƉƌĞƐƐŝŽŶ͕ƐƵďƐĞƋƵĞŶƚůLJĂůĚŽƐƚĞƌŽŶĞƉƌŽĚƵĐƚŝŽŶĂŶĚƉƌŽͲ ůŝĨĞƌĂƚŝŽŶ͘ͿůƚĞƌĂƚŝŽŶƐŝŶEϭĂŶĚEϭ,ĂůůŽǁĨŽƌĂϮнŝŶĨůƵdžĂƚŵŽƌĞŚLJƉĞƌƉŽůĂƌŝnjĞĚŵĞŵďƌĂŶĞ ƉŽƚĞŶƚŝĂůƐ͕ ƉƌŽŵŽƚŝŶŐ zWϭϭϮ ĞdžƉƌĞƐƐŝŽŶ͕ ĂůĚŽƐƚĞƌŽŶĞ ƉƌŽĚƵĐƚŝŽŶ ĂŶĚ ƉƌŽůŝĨĞƌĂƚŝŽŶ͘ Ϳ EĂнŽƌ,нŝŶĨůƵdž ƚŚƌŽƵŐŚŵƵƚĂŶƚdWϭϭůĞĂĚƐƚŽŵĞŵďƌĂŶĞĚĞƉŽůĂƌŝnjĂƚŝŽŶĂŶĚƚŚĞƌĞĨŽƌĞƚŚĞŽƉĞŶŝŶŐŽĨǀŽůƚĂŐĞͲŐĂƚĞĚĐĂůͲ ĐŝƵŵĐŚĂŶŶĞůƐ͘dŚĞƌĞƐƵůƚŝŶŐĂϮнŝŶĨůƵdžůĞĂĚƐƚŽzWϭϭϮĞdžƉƌĞƐƐŝŽŶ͕ĂůĚŽƐƚĞƌŽŶĞƉƌŽĚƵĐƚŝŽŶĂŶĚƉƌŽůŝĨĞƌĂͲ ƚŝŽŶ͘&ͿEĂнŝŶĨůƵdžƚŚƌŽƵŐŚŵƵƚĂŶƚdWϮϯŝŶĚƵĐĞƐĂůĚŽƐƚĞƌŽŶĞƉƌŽĚƵĐƚŝŽŶĂŶĚƉƌŽůŝĨĞƌĂƚŝŽŶŝŶĂƐŝŵŝůĂƌĨĂƐŚͲ ŝŽŶĂƐŵƵƚĂŶƚdWϭϭ͘ĞĐƌĞĂƐĞĚĂϮнĐůĞĂƌĂŶĐĞďLJƚŚĞŵƵƚĂŶƚƉƌŽƚĞŝŶŵŝŐŚƚĐŽŶƚƌŝďƵƚĞƚŽƚŚĞƐĞĞĨĨĞĐƚƐ͘ ĚĂƉƚĞĚĨƌŽŵŚŽŝĞƚĂů͕͘ϮϬϭϭ͕KŬŝĞƚĂů͕͘ϮϬϭϮ͕ĞƵƐĐŚůĞŝŶĞƚĂů͕͘ϮϬϭϯ͕njŝnjĂŶĞƚĂů͕͘ϮϬϭϯ͕<ŽƌĂŚĂŶĚ^ĐŚŽůů ϮϬϭϱ͕ dĂƵďĞƌ Ğƚ Ăů͕͘ ϮϬϭϲ͕ ^ĞŝĚĞů ĂŶĚ ^ĐŚŽůů͕ ϮϬϭϲ͕ ĂŶĚ ƵŶĚĞƌ ĐŽŶƐŝĚĞƌĂƚŝŽŶ ŽĨ ŝ >ĞǀĂ Ğƚ Ăů͕͘ ϮϬϬϴϭϵϳ͕ϮϬϭ͕Ϯϰϰ͕Ϯϲϵ͕ϮϳϬ͕ϮϳϵʹϮϴϭ͘ 

͵͸ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ —–ƒ–†‹•’Žƒ›Š‹‰Š‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•ǡŽ‹‡Ž› ƒ—•‡†„›ƒʹΪ‹ˆŽ—š–Š”‘—‰Š˜‘Ž–Ǧ ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•†—‡–‘†‡’‘Žƒ”‹œƒ–‹‘ƒ•™‡ŽŽƒ•”‡†— ‡†ƒʹΪ Ž‡ƒ”ƒ ‡„› –Š‡—–ƒ–ƒ•‡ǤŠ‡—–ƒ– ‡ŽŽ•ƒŽ•‘•Š‘™‡†‹ ”‡ƒ•‡†CYP11B2‡š’”‡••‹‘ƒ† ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ʹͺͳȋ ‹‰—”‡ͷ ȌǤ

6.3.2.1.4CTNNB1 mutations in aldosterone-producing adenomas ‘ƒ–‹ —–ƒ–‹‘•‹–Š‡‰‡‡‡ ‘†‹‰„‡–ƒǦ ƒ–‡‹ ȋCTNNB1ȌŠƒ˜‡„‡‡ˆ‘—†‹ †‹ˆˆ‡”‡––›’‡•‘ˆƒ†”‡‘ ‘”–‹ ƒŽƒ†‡‘ƒ•ȋ‹Ǥ‡Ǥǣ•ǡ ‘”–‹•‘ŽǦ•‡ ”‡–‹‰ƒ† ‘Ǧˆ— –‹‘ƒŽȌƒ•™‡ŽŽƒ•ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒȋˆ‘”ˆ”‡“—‡ ‹‡•‹• ‘’ƒ”‡ ƒ„Ž‡ͳȌǤ‹ˆˆ‡”‡––›’‡•‘ˆ—–ƒ–‹‘•ȋ•—„•–‹–—–‹‘•ǡ†‡Ž‡–‹‘•ƒ†‹•‡”–‹‘•ȌŠƒ˜‡ „‡‡‹†‡–‹ˆ‹‡†ǡƒŽŽ‘ˆ–Š‡ƒˆˆ‡ –‹‰‡š‘͵‘ˆ–Š‡‰‡‡ǤŠ‡”‡•‹†—‡Ͷͷ‹•–Š‡‘•– ˆ”‡“—‡–Ž›ƒŽ–‡”‡†‘‡‹‹••‡•‡—–ƒ–‹‘•ʹͶͷǡʹ͹ͳǡʹͺʹȋƒ„Ž‡ʹȌǤŠ‡ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡ ʹͻͷŠƒ”„‘”•ƒS45P—–ƒ–‹‘‹–Š‡CTNNB1‰‡‡ǡ™Š‹ Š™ƒ• •—‰‰‡•–‡†–‘Ž‡ƒ†–‘ ‘•–‹–—–‹˜‡ƒ –‹˜ƒ–‹‘‘ˆ–Š‡™–’ƒ–Š™ƒ›ʹͶͷǡʹͺʹǤ”‡ ‡–•–—†›‘ˆ ͳͻͺ • Šƒ• †‡• ”‹„‡† ƒ —–ƒ–‹‘ ˆ”‡“—‡ › ‘ˆ ͷǤͳΨǡ ™Š‹ Š ”‡ƒ‹• ‘’ƒ”ƒ„Ž‡ ƒ‘‰†‹ˆˆ‡”‡–ƒ–‹‘ƒŽ ‘Š‘”–•Ǥ –Š‹•”‡’‘”–ǡ–—‘”•™‹–ŠCTNNB1—–ƒ–‹‘™‡”‡ ƒŽ•‘ˆ‘—†–‘„‡•‹‰‹ˆ‹ ƒ–Ž›Žƒ”‰‡”–Šƒ–Š‘•‡™‹–Š‘—–‘™—–ƒ–‹‘•Ǥ  ”‡ƒ•‡† ‡š’”‡••‹‘‘ˆAXIN2ǡŠ‹–‹‰ƒ–ƒ –‹˜ƒ–‹‘‘ˆ–Š‡™–’ƒ–Š™ƒ›ǡ™ƒ•ˆ‘—†‹–—‘”• ™‹–ŠCTNNB1—–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‘•‡™‹–ŠKCNJ5—–ƒ–‹‘ʹ͹ͳǤ‘–Š‡”•–—†› ’—„Ž‹•Š‡†‹ʹͲͳ͹ˆ‘—†ƒ—–ƒ–‹‘ˆ”‡“—‡ ›‘ˆ͵Ǥ͹Ψ‹ƒ ‘Š‘”–‘ˆʹͳͻ•ʹ͹͸Ǥ – ”‡’‘”–•‘Ž†‡”ƒ‰‡‘ˆ’ƒ–‹‡–•™‹–ŠCTNNB1‹ ‘’ƒ”‹•‘–‘KCNJ5—–ƒ–•Ǥ —”Ǧ –Š‡”‘”‡ǡ’ƒ–‹‡–•™‹–Š• ƒ””›‹‰CTNNB1—–ƒ–‹‘•Šƒ†ƒ‹ ”‡ƒ•‡†”‹•‘ˆ”‡Ǧ •‹†—ƒŽŠ›’‡”–‡•‹‘ƒˆ–‡”ƒ†”‡ƒŽ‡ –‘›‹ ‘’ƒ”‹•‘–‘’ƒ–‹‡–•™‹–Š™‹Ž†–›’‡‘” KCNJ5—–ƒ––—‘”•ʹ͹͸Ǥˆ‘–‡ǡCTNNB1 —–ƒ–‹‘•™‡”‡‘–‘Ž›„‘–Šˆ‘—†‹ƒ”‡ƒ• ‡š’”‡••‹‘CYP11B2’‘•‹–‹˜‡ƒ†‡‰ƒ–‹˜‡ƒ”‡ƒ•„—–ƒŽ•‘‹ ‡ŽŽ•‡š’”‡••‹‰–Š‡ͳͳȾǦ Š›†”‘š›Žƒ•‡‰‡‡CYP11B1ǡ ”— ‹ƒŽˆ‘” ‘”–‹•‘Ž’”‘†— –‹‘‹–Š‡ƒ†”‡ƒŽ ʹʹǡʹ͹͸ǤŠ‹• ‹†‹ ƒ–‡•–Šƒ––Š‡”‘Ž‡‘ˆCTNNB1—–ƒ–‹‘•‹•‹‰Š–’”‹ƒ”‹Ž›„‡„ƒ•‡†‘‹–• ’”‘Ǧ’”‘Ž‹ˆ‡”ƒ–‹˜‡‡ˆˆ‡ –•ǡŽ‡ƒ†‹‰–‘–—‘”ˆ‘”ƒ–‹‘ǡ‹•–‡ƒ†‘ˆ†‹”‡ –Ž›ƒˆˆ‡ –‹‰ƒŽ†‘•Ǧ –‡”‘‡’”‘†— –‹‘ʹ͹͸Ǥ

‹ ‡ǡ ‘•–‹–—–‹˜‡„‡–ƒǦ ƒ–‡‹ƒ –‹˜ƒ–‹‘™ƒ••Š‘™–‘Ž‡ƒ†–‘‹ ”‡ƒ•‡†ƒ†”‡ƒŽ ’”‘Ž‹ˆ‡”ƒ–‹‘ǡŠ›’‡”’Žƒ•‹ƒƒ††›•’Žƒ•‹ƒǡƒ•™‡ŽŽƒ•’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•‘˜‡” –‹‡Ǥ˜‡”ƒ‡š–‡†‡†–‹‡•’ƒǡ–”ƒ•‰‡‹ —”‹‡ƒ†”‡ƒŽ‰Žƒ†•†‡˜‡Ž‘’‡†ƒŽ‹‰Ǧ ƒ– Šƒ”ƒ –‡”‹•–‹ •ʹͺ͵Ǥ

͵͹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ –Š‡‹”ʹͲͳͷ•–—†›ǡ‡‘etal.”‡’‘”–‡†‹ ”‡ƒ•‡†Ž‡˜‡Ž•Ž—–‡‹‹œ‹‰Š‘”‘‡Ȃ Š‘”‹‘‹  ‰‘ƒ†‘–”‘’‹ ”‡ ‡’–‘” ȋ Ǧ Ȍ ƒ† ‰‘ƒ†‘–”‘’‹Ǧ”‡Ž‡ƒ•‹‰ Š‘”‘‡ ”‡ ‡’–‘” ȋ  Ȍ‹–Š”‡‡ˆ‡ƒŽ‡’ƒ–‹‡–•™‹–ŠCTNNB1—–ƒ–‡†•Ǥ ‹–Š‡•‡’ƒ–‹‡–• ƒ‹ˆ‡•–‡† ‡‹–Š‡” †—”‹‰ ’”‡‰ƒ › ‘” ‡‘’ƒ—•‡ǡ •‹–—ƒ–‹‘• ‰‡‡”ƒŽŽ› ƒ”‡† „› Š‹‰Š ‘ ‡–”ƒ–‹‘• ‘ˆ ‹” —Žƒ–‹‰ Š‘”‹‘‹  ‰‘ƒ†‘–”‘’‹ǡ Ž—–‡‹‹œ‹‰ Š‘”‘‡ǡ ‘” ‰‘ƒ†‘–”‘’‹Ǧ”‡Ž‡ƒ•‹‰Š‘”‘‡ʹͺͶǤ  ”‡ƒ•‡†‡š’”‡••‹‘‘ˆ”‡ ‡’–‘”•ˆ‘”Ž—–‡‹‹œ‹‰ Š‘”‘‡ƒ†‰‘ƒ†‘–”‘’‹Ǧ”‡Ž‡ƒ•‹‰Š‘”‘‡‹•‘ˆ—‘™—–ƒ–‹‘ƒŽ•–ƒ–—• Šƒ˜‡„‡‡†‡• ”‹„‡†’”‡˜‹‘—•Ž›ʹͺͷȂʹͺ͹ǤInvitro•–—†‹‡•—•‹‰ ʹͻͷ ‡ŽŽ•‹’Ž‹ ƒ–‡Ž—Ǧ –‡‹‹œ‹‰ Š‘”‘‡ ƒ† ‰‘ƒ†‘–”‘’‹Ǧ ”‡Ž‡ƒ•‹‰ Š‘”‘‡ ƒ• ’‘•‹–‹˜‡ ”‡‰—Žƒ–‘”• ‘ˆ CYP11B2‡š’”‡••‹‘ʹͺͷǡʹͺ͹Ǥ ‘™‡˜‡”ǡ‹–•Š‘—Ž†„‡‘–‡†–Šƒ–CTNNB1—–ƒ–‹‘•Šƒ˜‡ „‡‡†‡–‡ –‡†‹•ˆ”‘„‘–Šˆ‡ƒŽ‡ƒ†ƒŽ‡’ƒ–‹‡–•ʹ͹ͳǡʹ͹͸Ǥ –‡”‡•–‹‰Ž›ǡ™Š‹Ž‡ —etal.”‡’‘”–‹ ”‡ƒ•‡†‡š’”‡••‹‘‘ˆ Ǧ ƒ†  ‹• ƒ””›‹‰CTNNB1 —–ƒ–‹‘•‹ ‘’ƒ”‹•‘–‘–Š‘•‡™‹–Š—–ƒ–KCNJ5ǡ–Š‡›ƒ‡–Š‹•‘„•‡”˜ƒ–‹‘‹ •ƒ’Ž‡•ˆ”‘„‘–Š•‡š‡•Ǥ —”–Š‡”‘”‡ǡ–Š‡› ‘ˆ‹”–Šƒ–”‡ ‡’–‘”‡š’”‡••‹‘‹•‘– —‹“—‡–‘CTNNB1—–ƒ––—‘”•ʹ͹͸Ǥˆ‘–‡ǡ‹–Š‡”‡Žƒ–‹˜‡Ž›Žƒ”‰‡ ‘Š‘”–’”‡•‡–‡† „›—etal.ǡˆ‡ƒŽ‡ ’ƒ–‹‡–•™‡”‡‘–†‹ƒ‰‘•‡††—”‹‰’”‡‰ƒ ›ǡ„—–ƒ–‘Ž†‡” ƒ‰‡ǡ‹Ǥ‡Ǥ†—”‹‰‡‘’ƒ—•‡‘”‹’‘•–Ǧ‡‘’ƒ—•‡ʹ͹͸Ǥ‘•‡“—‡–Ž›ǡ ƒ•‡•‘ˆCTNNB1 —–ƒ–•ƒ‹ˆ‡•–‹‰†—”‹‰’”‡‰ƒ ›ǡƒ•†‡• ”‹„‡†‹–Š‡•–—†›„›‡‘etal., ™Š‹ Š ‘’”‹•‡†‘Ž›–Š”‡‡•—„Œ‡ –•ǡ•‡‡–‘„‡”ƒ–Š‡”•‹‰—Žƒ”‡˜‡–•ʹ͹͸ǡʹͺͺǤŠ‹•‹•‹ Ž‹‡™‹–Šƒ ‘‡–‹™Š‹ Š”‡•‡ƒ” Š‡”••–ƒ–‡–Šƒ–’”‡‰ƒ ›†‹†‘–’Žƒ›ƒ”‘Ž‡‹ –Š‡ ƒ•‡•‘ˆCTNNB1—–ƒ–•–Š‡›Šƒ˜‡‡ ‘—–‡”‡†ʹͺͻǤ

6.3.2.1.5APAoriginsandtheroleofaldosteroneǦproducingcellclusters ‘ˆƒ”ǡ‘—”—†‡”•–ƒ†‹‰‘ˆˆ‘”ƒ–‹‘‹•Ž‹‹–‡†Ǥ‘–ƒ„Ž›ǡƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ‡ŽŽ Ž—•–‡”•ȋ•ȌŠƒ˜‡„‡‡•—‰‰‡•–‡†–‘’Žƒ›ƒ”‘Ž‡‹†‡˜‡Ž‘’‡–ǤŠ‡›ƒ”‡ Ž—•–‡”•‘ˆ ‡ŽŽ•Ž‘ ƒ–‡†”‹‰Š–„‡Ž‘™–Š‡ƒ†”‡ƒŽ ƒ’•—Ž‡ǡ™Š‹ Šƒ”‡ƒ”‡†„›Š‹‰Š‡šǦ ’”‡••‹‘Ž‡˜‡Ž•‘ˆCYP11B2ʹͻͲǡʹͻͳǤŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡•‡ ‡ŽŽ•Šƒ•„‡‡•—‰Ǧ ‰‡•–‡†–‘„‡ƒ—–‘‘‘—•ǡ‹Ǥ‡Ǥ‹†‡’‡†‡–‘ˆ”‡‰—Žƒ–‹‘„›–Š‡ʹͻͲǤǦƒ••‘ ‹Ǧ ƒ–‡†•‘ƒ–‹ —–ƒ–‹‘•‹ATP1A1ƒ†CACNA1D—–ƒ–‹‘•Šƒ˜‡„‡‡‹†‡–‹ˆ‹‡†‹ –Š‡•‡ ‡ŽŽƒ‰‰”‡‰ƒ–‡•ǡ•—‰‰‡•–‹‰–Šƒ––Š‡›‹‰Š–„‡’”‘‰‡‹–‘”•‘ˆƒ–Ž‡ƒ•–ƒ•—„•‡–‘ˆ •ʹͻͳǤ”‡ ‡–”‡’‘”–†‡• ”‹„‡• ‘–ƒ‹‹‰ƒ‹ ”‘’‘”–‹‘ǡ™Š‹ Š™‡”‡ ‹–‡”’”‡–‡†ƒ•ƒ’‘••‹„Ž‡–”ƒ•‹–‹‘ƒŽ•–ƒ‰‡„‡–™‡‡•ƒ†•Ǥ —–ƒ–‹‘• ‹ ‰‡‡•‹’Ž‹ ƒ–‡†‹•™‡”‡ˆ‘—†‹–Š‡’‘”–‹‘ǡ„—–‘–‹–Š‡’‘”–‹‘ ‘ˆ–™‘Žƒ”‰‡–”ƒ•‹–‹‘ƒŽŽ‡•‹‘•ȋ‘—–‘ˆ–Š”‡‡Ȍǡ•—‰‰‡•–‹‰–Š‡‹”

͵ͺ   ƚŝĨŝĞĚƚŚƌŽƵŐŚŽƵƚ  ͻ ‹ˆ”ƒ‡†‡Ž‡–‹‘•‘•–ˆ”‡Ǧ ĂŶĚƵƚƚĂ͕^ƂĚĞƌŬǀŝƐƚĂŶĚ'ƌŝŵŵ͕ ϯϱϭ Ž›–™‘Žƒ”‰‡•–—†‹‡•ƒ˜ƒ‹Žƒ„Ž‡ ‘’ƒ”‹‰’ƒ–‹‡–ƒ†–—‘” Šƒ”Ǧ ƒ –‡”‹•–‹ • “—‡–Ž›ƒˆˆ‡ –Ͷʹͷƒ†Ͷʹ͸ ‡•–‡” ‘Š‘”–•ǣŠ‹‰Š‡”ˆ”‡“—‡ › ȋ̱ͺΨȌ  ‘Š‘”–•ǣŠ‹‰Š‡”—–ƒ–‹‘ˆ”‡Ǧ “—‡ ›ȋ̱͹ͲΨȌ ͸͹   ‘Š‘”–•ǣŽ‘™‡”ˆ”‡“—‡ ›ȋ̱ʹΨȌ „ ĚŝĞƐ͕ƚŚĞŵŽƐƚĨƌĞƋƵĞŶƚůLJƌĞĐƵƌƌĞŶƚŵƵƚĂƚŝŽŶƐĂƐǁĞůůĂƐ Ȁ ‘’ƒ”‡†–‘™–ƒ† ĚŝĞƐůŝƐƚĞĚŝŶdĂďůĞϲ͕dĂďůĞϳ͕dĂďůĞϴĂŶĚdĂďůĞϵ;ƐĞĐƚŝŽŶ —‘” Š‹•–‘Ž‘‰›  ͘ Ȁ  ǦŽ‹‡ Ϯϰϵ͕Ϯϲϵ „ „ ‡ ‡   •‡˜‡”‹–› ƌƐƌĞƉŽƌƚĞĚ Ȁ Ȁ „ „ ǁŝƚŚ'ϰϬϯZďĞŝŶŐƚŚĞŵŽƐƚĐŽŵŵŽŶŽŶĞ;ŵƵƚĂƚŝŽŶƐŚĂǀĞďĞĞŶŝĚĞŶ •‹œ‡  ŵƵƚĂŶƚWƐ͘>ĂLJŽƵƚĂĚĂƉƚĞĚĨƌŽŵ^ƚŽǁĂƐƐĞƌ͕ϮϬϭϯ Eϭ <E:ϱ Ȁ Ȁ „ „ Ȁ Ȁ ƚĂƚŝƐƚŝĐĂůůLJƐŝŐŶŝĨŝĐĂŶƚďLJĚŝĨĨĞƌĞŶƚƐƚƵĚŝĞƐ͘ĂƐĞĚŽŶƚŚĞƐƚƵ ‡š ‰‡  „‹ƒ• ƒŽ‡ ‘ˆ–‡ ˆ‡ƒŽ‡ ›‘—‰‡” Žƒ”‰‡” Š‹‰Š‡”  ǦŽ‹‡ ‘’ƒ”‡†–‘™– ƉƉƌŽdžŝŵĂƚĞŵĞĂŶĨƌĞƋƵĞŶĐŝĞƐŽĨƐŽŵĂƚŝĐŵƵƚĂƚŝŽŶƐŝŶůĂƌŐĞƌƐƚƵ ‡’‡ƒ–‡†Ž›”‡’‘”–‡†’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ • ‘‡– ‘ˆ‡ƒŽ‡ ĨŽƌ&ͲůŝŬĞĂƉƉĞĂƌĂŶĐĞŽĨ Ϯϱϴ     ƒ ƒ ƒ ƒ ͕ϮϬϭϱ ĞƚĂů͘ –‹‘• ͳ͸ͺ Ͷ͹Ͷ ͹ͷͲ —–ƒ–‹‘• ʹ͵†‡Ž‡Ǧ ŵƵƚĂƚŝŽŶƐĐŽŵďŝŶĞĚŵĂůĞƉƌĞǀĂůĞŶĐĞ͕ŽůĚĞƌĂŐĞĂŶĚƐŵĂůůĞƌƚƵŵŽ ‘•– ‘‘ ƚŚĞƚŚƌĞĞŵŽƐƚĨƌĞƋƵĞŶƚůLJƌĞƉŽƌƚĞĚŵƵƚĂƚŝŽŶƐŝŶ Ă ͖DŽŶƚŝĐŽŶĞ Ϯϱϳ Eϭ ̱ͶΨ Ͷͷ ‘„‹ƒ• Ȁ Ȁ ‘†‹ˆˆ‡”Ǧ ̱ͷΨ ͶͲ͵ ϮϬϭϮ ̱ͶͲΨ ͳͷͳ ‘Š‘”–• ‹Žƒ”‰‡” ĞƚĂů͘ ĨŽƌdWĂƐĞĂŶĚ ď  ͘ Ϯϰ ͷ ƒ•‡ ̱͸Ψ ͳͳͳͲͶ  ͻ ‡‡ ”‡“—‡ › ͷ ƚŚĞŐĞŶĞͿ͕ ϮϬϭϲ ϭϭ͘ϱͿĂŶĚnjŝnjĂŶ dĂďůĞϮ͘'ĞŶĞŵƵƚĂƚŝŽŶƐŝŶWƐĂŶĚƚŚĞŝƌĐŚĂƌĂĐƚĞƌŝƐƚŝĐƐ͘ EͬŶŽƚĂǀĂŝůĂďůĞ͕͗ĂƐƚƐŝĂŶ͕ ĚŝƐƚŝŶĐƚŝǀĞƉĂƚŝĞŶƚĂŶĚƚƵŵŽƌĨĞĂƚƵƌĞƐƌĞƉĞĂƚĞĚůLJƌĞƉŽƌƚĞĚĂƐƐ ͵ͻ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ”‡Ž‡˜ƒ ‡‹–‘’”‘‰”‡••‹‘ʹͻʹǤ‘–ƒ„Ž›ǡ‘‡‘ˆ–Š‡•‡—–ƒ–‹‘•™ƒ•KCNJ5 G151Rǡ–Š‡‘•–ˆ”‡“—‡–—–ƒ–‹‘‹•ʹͻʹȋ ‘’ƒ”‡ƒ„Ž‡ʹȌǤ

6.3.2.2 Familial hyperaldosteronism Š‡”‹–‡†ˆ‘”•‘ˆŠ›’‡”ƒŽ†‘•–‡”‘‹•Šƒ˜‡„‡‡–”ƒ ‡†„ƒ –‘‰‡”Ž‹‡—–ƒ–‹‘• ‹ƒ˜ƒ”‹‡–›‘ˆ‰‡‡•Ǥ ‘ Šƒ‡Ž—–ƒ–‹‘•‹†‡–‹ˆ‹‡†‹ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹• ƒ† ‡–”ƒŽ’ƒ–‹‡– Šƒ”ƒ –‡”‹•–‹ •ƒ”‡Ž‹•–‡†‹ƒ„Ž‡͵Ǥ

6.3.2.2.1Glucocorticoid-remediable hyperaldosteronism – crossing-over be- tween CYP11B1 and CYP11B2 Š‡ˆ‘”–Šƒ–Šƒ•„‡‡‘™–Š‡Ž‘‰‡•–‹•‰Ž— ‘ ‘”–‹ ‘‹†Ǧ”‡‡†‹ƒ„Ž‡Š›’‡”ƒŽ†‘•–‡Ǧ ”‘‹•ȋ ȌƒŽ•‘”‡ˆ‡””‡†–‘ƒ•ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ȋ  ȌǤ –™ƒ•ˆ‹”•– †‡• ”‹„‡†‹ͳͻ͸͸‹ƒˆƒ–Š‡”ƒ†•‘™‹–ŠŠ›’‡”–‡•‹‘ǡ‡Ž‡˜ƒ–‡†ƒŽ†‘•–‡”‘‡ƒ†•—’Ǧ ’”‡••‡†”‡‹Ž‡˜‡Ž•ƒ•™‡ŽŽƒ•Š›’‘ƒŽ‡‹ƒǡ™Š‹ Š™‡”‡”‡Ž‹‡˜‡†„›ƒ†‹‹•–”ƒ–‹‘‘ˆ †‡šƒ‡–Šƒ•‘‡ʹ͹ͻǡʹͻ͵Ǥ Ž— ‘ ‘”–‹ ‘‹†”‡‡†‹ƒ„Ž‡Š›’‡”ƒŽ†‘•–‡”‘‹•‹•˜‡”›”ƒ”‡ǡƒˆǦ ˆ‡ –‹‰δͳΨ‘ˆ  ƒ•‡•ʹ͵ͺǤ –‹•‹Š‡”‹–‡†‹ƒƒ—–‘•‘ƒŽ†‘‹ƒ–ˆƒ•Š‹‘ƒ†ƒˆǦ ˆ‡ –•‡ƒ†™‘‡‡“—ƒŽŽ›Ǥ•‡–‘ˆŠ›’‡”–‡•‹‘‹•‡ƒ”Ž›ǡ—•—ƒŽŽ›„›–Š‡ƒ‰‡‘ˆʹͲǤ ƒ–‹‡–• ƒŽ•‘ Šƒ˜‡ ƒ ‹ ”‡ƒ•‡† ”‹• ‘ˆ ‡”‡„”ƒŽ Š‡‘””Šƒ‰‡ǡ ‘ˆ–‡ Ž‡ƒ†‹‰ –‘ †‡ƒ–Šʹ͹ͻǡʹͻͶǤ ‡‡–‹ ƒŽŽ›ǡ–Š‡†‹•‘”†‡”‹•„ƒ•‡†‘ƒ ”‘••‹‰Ǧ‘˜‡”‡˜‡–„‡–™‡‡–Š‡ ‰‡‡• CYP11B2ƒ†CYP11B1ǡ ƒ—•‹‰ ƒŽ†‘•–‡”‘‡Ǧ•›–Šƒ•‡ –‘ „‡ ‡š’”‡••‡† —†‡” ‘–”‘Ž‘ˆ–Š‡CYP11B1’”‘‘–‡”ǡƒ†–Š‡”‡ˆ‘”‡—†‡””‡‰—Žƒ–‹‘‘ˆ ‹–Š‡ ‘ˆ –Š‡ ƒ†”‡ƒŽ ‰Žƒ†ʹͻͷǡʹͻ͸Ǥ †‹‹•–”ƒ–‹‘ ‘ˆ †‡šƒ‡–Šƒ•‘‡ Ž‡ƒ†• –‘ •—’’”‡••‹‘ ‘ˆ  ƒ†ƒ ‘”†‹‰Ž›ǡ‹–Š‡•‡’ƒ–‹‡–•ǡ–‘”‡†— –‹‘‘ˆƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•ʹͻͶǤŠ‡†‹Ǧ ƒ‰‘•‹• ƒ„‡ ‘ˆ‹”‡†˜‹ƒƒ’Ž‹ˆ‹ ƒ–‹‘‘ˆ–Š‡—–ƒ–‡†‰‡‡ʹͻ͹Ǥ ”‡’‘”–‡†Ž› Šƒ•ƒ‹ ”‡ƒ•‡†’”‡˜ƒŽ‡ ‡ƒ‘‰’‡‘’Ž‡‘ˆ ”‹•Šƒ ‡•–”›ʹͻ͸Ǥ

6.3.2.2.2Familial hyperaldosteronism type II – familial hyperaldosteronism with unknown causes ˆ–‡”–Š‡†‹• ‘˜‡”›‘ˆ ǡ‡˜‹†‡ ‡‘ˆ‘–Š‡”ˆ‘”•‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹• ‡‡”‰‡†ǡ™Š‹ Š™‡”‡‘–”‡‡†‹ƒ„Ž‡„›ƒ†‹‹•–”ƒ–‹‘‘ˆ†‡šƒ‡–Šƒ•‘‡ʹͻͺȂ͵ͲͳǤ  ‘”†‡”–‘†‹•–‹‰—‹•Š„‡–™‡‡–Š‡†‹ˆˆ‡”‡–ˆƒ‹Ž‹ƒŽˆ‘”•‘ˆ ǡ–Š‡–‡”ˆƒ‹Ž‹ƒŽŠ›Ǧ ’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ȋ  Ȍ™ƒ•‡•–ƒ„Ž‹•Š‡†ʹͻͻǤ –”‡ˆ‡”•–‘ˆƒ‹Ž‹ƒŽ ƒ•‡•‘ˆŠ›’‡”Ǧ ƒŽ†‘•–‡”‘‹• ‹ ™Š‹ Š –Š‡ —†‡”Ž›‹‰ ƒ—•‡ Šƒ• ‘– „‡‡ ‹†‡–‹ˆ‹‡† ȋ ‘’ƒ”‡ ‡Ǥ‰Ǥ ʹ͵ͳǡʹͶͲǡʹ͹ͻȌǤ –‹ Ž—†‡•„‘–Š’ƒ–‹‡–•™‹–Š•ƒ•™‡ŽŽƒ•„‹Žƒ–‡”ƒŽŠ›’‡”’Žƒ•‹ƒʹͶͲǡʹͻͺǤ Š‡› ƒ”‡ ˜‹”–—ƒŽŽ› ‹†‹•–‹‰—‹•Šƒ„Ž‡ ˆ”‘ ‘Ǧˆƒ‹Ž‹ƒŽ ƒ•‡•ʹͶͲǡʹͻͺǡ͵ͲʹǤ   ™ƒ• ”‡Ǧ

ͶͲ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ’‘”–‡†–‘„‡‘”‡’”‡˜ƒŽ‡––Šƒ  ʹ͵ͳǡʹͶͲǤŠ‹•‹•ƒ–Ž‡ƒ•–‹’ƒ”–ƒ”‡•—Ž–‘ˆ–Š‡”‡ŽƒǦ –‹˜‡Ž›”‡Žƒš‡††‹ƒ‰‘•‹• ”‹–‡”‹ƒƒ’’Ž‹‡†ˆ‘”  ǡ‹ Ž—†‹‰ ƒ•‡•‘ˆƒ†„‹Žƒ–‡”ƒŽ Š›’‡”’Žƒ•‹ƒ ƒ† •‹’Ž› ˆ‘ —•‹‰ ‘ —Ž–‹’Ž‡ ‘ —””‡ ‡• ‘ˆ  ™‹–Š‹ ‘‡ˆƒ‹Ž› ™‹–Š‘—–”‡“—‹”‹‰‹†‡–‹ˆ‹ ƒ–‹‘‘ˆ ‘‘—†‡”Ž›‹‰‰‡‡–‹ •ʹ͹ͻǤ’”‹ƒ”‹Ž›ƒ—–‘Ǧ •‘ƒŽ†‘‹ƒ–‘†‡‘ˆ‹Š‡”‹–ƒ ‡Šƒ•„‡‡•—‰‰‡•–‡†ʹͻͺǡ͵Ͳ͵ǡ͵ͲͶǤ‹ƒ‰‡ƒƒŽ›•‹•Šƒ• –‹‡†  –‘–Š‡ Š”‘‘•‘ƒŽŽ‘ —•͹’ʹʹǡ„—–™‹–Š‘—–‹†‡–‹ˆ›‹‰ ƒ—•ƒŽ˜ƒ”‹ƒ–•͵Ͳ͵Ȃ ͵ͲͷǤ ‘™‡˜‡”ǡ‰‡‡–‹ Š‡–‡”‘‰‡‡‹–›Šƒ•„‡‡•—‰‰‡•–‡†͵ͲͶǤ



&ŝŐƵƌĞϲ͘&ƌĞƋƵĞŶƚůLJŵƵƚĂƚĞĚƌĞƐŝĚƵĞƐŝŶŝŽŶĐŚĂŶŶĞůƐŝŵƉůŝĐĂƚĞĚŝŶW,ĂŶĚƚŚĞŝƌƉŽƐŝƚŝŽŶǁŝƚŚŝŶĞĂĐŚ ƉƌŽƚĞŝŶ͘Ϳ<E:ϱ'ϭϱϭZŝƐůŽĐĂƚĞĚŝŶďĞƚǁĞĞŶƚŚĞƉŽƌĞŚĞůŝdžĂŶĚdDϮĂŶĚ>ϭϲϴZŝƐůŽĐĂƚĞĚŝŶƚŚĞƵƉƉĞƌƉĂƌƚ ŽĨdDϮ͕ǁŚŝĐŚůŽĐĂůŝnjĞƐďŽƚŚŵƵƚĂƚŝŽŶƐŶĞĂƌƚŚĞƐĞůĞĐƚŝǀŝƚLJĨŝůƚĞƌŽĨƚŚĞĐŚĂŶŶĞůƉŽƌĞ͘ͿdWϭϭ>ϭϬϰŝƐůŽͲ ĐĂƚĞĚŝŶƚŚĞDϭŚĞůŝdžŽĨƚŚĞƉƌŽƚĞŝŶ͘dWϮϯ>ϰϮϱͲsϰϮϲĂƌĞůŽĐĂƚĞĚ ŝŶ ƚŚĞ Dϰ ŚĞůŝdž ŽĨ ƚŚĞ ĐŚĂŶŶĞů͘ Ϳ Eϭ'ϰϬϯŝƐůŽĐĂƚĞĚŝŶƐĞŐŵĞŶƚ^ϲŽĨƌĞƉĞĂƚ/ĂŶĚEϭ&ϳϰϳĂŶĚ/ϳϱϬĂƌĞůŽĐĂƚĞĚŝŶƐĞŐŵĞŶƚ^ϲ ŽĨƌĞƉĞĂƚ//͘dŚĞŵƵƚĂƚŝŽŶƐĚĞƉŝĐƚĞĚŚĞƌĞƌĞƉƌĞƐĞŶƚƚŚĞƚŚƌĞĞŵŽƐƚĐŽŵŵŽŶŵƵƚĂƚŝŽŶƐŝŶEϭ͘EĞǀĞƌͲ ƚŚĞůĞƐƐ͕ŵƵƚĂƚŝŽŶƐŚĂǀĞďĞĞŶĚŝƐĐŽǀĞƌĞĚƚŚƌŽƵŐŚŽƵƚƚŚĞŐĞŶĞ;ĐŽŵƉĂƌĞdĂďůĞϳͿ͘ͿEϭ,DϭϱϰϵŝƐ ůŽĐĂƚĞĚ ŝŶ ƐĞŐŵĞŶƚ ^ϲ ŽĨ ƌĞƉĞĂƚ ///͘ ĚĂƉƚĞĚ ĨƌŽŵ ƵƚƚĂ͕ ^ƂĚĞƌŬǀŝƐƚ ĂŶĚ 'ƌŝŵŵ͕ ϮϬϭϲ͕ ŚŽŝ Ğƚ Ăů͘ ϮϬϭϭ͕ ĞƵƐĐŚůĞŝŶĞƚĂů͘ϮϬϭϯ͕^ĐŚŽůůĞƚĂů͕͘ϮϬϭϯ͕^ĐŚŽůůĞƚĂů͕͘ϮϬϭϱĂŶĚĂŶŝŝůĞƚĂů͕͘ϮϬϭϲϮϰ͕ϭϭϱ͕ϭϭϴ͕ϭϮϭ͕ϭϵϳ͕Ϯϰϰ͘

Ͷͳ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ 6.3.2.2.3Familial hyperaldosteronism type III – KCNJ5 germline mutations ‹–Š–Š‡”‹•‡‘ˆ‡š–‰‡‡”ƒ–‹‘•‡“—‡ ‹‰ǡ‹–™ƒ•’‘••‹„Ž‡–‘•Š‡†ˆ—”–Š‡”Ž‹‰Š–‘–Š‡ —†‡”Ž›‹‰‰‡‡–‹ •‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•ǡ‡•’‡ ‹ƒŽŽ›–Š”‘—‰Š‹†‡–‹ˆ‹ ƒ–‹‘ ‘ˆ ƒ†‹†ƒ–‡‰‡‡•‡•–ƒ„Ž‹•Š‡†‹‹˜‡•–‹‰ƒ–‹‘•‘ˆ•ʹ͹ͻǤ ƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘Ǧ ‹•–›’‡ ȋ  Ȍ‹•ƒ‹Š‡”‹–ƒ„Ž‡ˆ‘”‘ˆ ƒ—•‡†„›—–ƒ–‹‘•‹KCNJ5ȋ ‘’ƒ”‡ ‡Ǥ‰Ǥʹ͹ͻȌǤ‡‘ˆ–Š‡‡ƒ”Ž‹‡” ƒ•‡•‘ˆ‘Ǧ‰Ž— ‘ ‘”–‹ ‘‹†”‡‡†‹ƒ„Ž‡ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•Ǧ –‡”‘‹•™ƒ•Žƒ–‡””‡Žƒ–‡†–‘–Š‡KCNJ5 T158A —–ƒ–‹‘ͳͻ͹ǡ͵Ͳ͸ǡ͵Ͳ͹ǤŠ‹•—–ƒ–‹‘‹•ƒŽ•‘ ‘ ƒ•‹‘ƒŽŽ›ˆ‘—†‹•ȋ ‘’ƒ”‡ʹͷʹǡʹ͹ͷǡ͵ͲͺȌǤ‹‡–Š‡‘•– ‘‘—–ƒ–‹‘•†‡Ǧ • ”‹„‡†‹•ǡ ͳͷͳƒ†ͳ͸ͺǡ‹–‹•Ž‘ ƒ–‡†‡ƒ”–Š‡•‡Ž‡ –‹˜‹–›ˆ‹Ž–‡”ƒ† ƒ—•‡• ƒΪ ‘†— –ƒ ‡‹–Š‡—–ƒ– Šƒ‡Žǡ™Š‹ ŠŽ‡ƒ†•–‘‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ƒ† ƒʹΪ‹ˆŽ—šͳͻ͹ǡʹͲ͵ǡ͵ͲͻǤ–—†‹‡•‹ƒ†”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡•Šƒ˜‡ƒŽ•‘ ‘ˆ‹”‡†–Šƒ– –”ƒ•ˆ‡ –‹‘™‹–Š–Š‡—–ƒ– Šƒ‡ŽŽ‡ƒ†•–‘‹ ”‡ƒ•‡†CYP11B2‡š’”‡••‹‘ƒ†ƒŽǦ †‘•–‡”‘‡’”‘†— –‹‘ǡ™Š‹ Š ƒ„‡”‡†— ‡†„›‹Š‹„‹–‘”•‘ˆ ƒŽ ‹—•‹‰ƒŽ‹‰ʹͲͳǡ͵ͳͲǤ –Š‡” KCNJ5—–ƒ–‹‘•ˆ‘—†‹ˆƒ‹Ž‹ƒŽˆ‘”•‘ˆŠ›’‡”ƒŽ†‘•–‡”‘‹•ƒ”‡G151R, I157S,ƒ†E145QǤƒ–‹‡–•™‹–Š–Š‡•‡—–ƒ–‹‘•—•—ƒŽŽ›’”‡•‡–™‹–Šƒ•‡˜‡”‡’Š‡‘Ǧ –›’‡ƒ†‰‡‡”ƒŽŽ›”‡“—‹”‡ƒ†”‡ƒŽ‡ –‘›ǡ•‹ ‡–Š‡›‘ˆ–‡•—ˆˆ‡”ˆ”‘ƒ••‹˜‡„‹Žƒ–Ǧ ‡”ƒŽŠ›’‡”’Žƒ•‹ƒƒ†–Š‡‹” ƒ‘–„‡ƒƒ‰‡†„›‡†‹ ƒ–‹‘ʹ͹ͻǡ͵ͳͳȂ͵ͳ͵ȋƒ„Ž‡͵ȌǤ ‰ƒ‹ǡ’ƒ–Š‘’Š›•‹‘Ž‘‰›‹•„ƒ•‡†‘ƒŽ‘••‘ˆΪ•‡Ž‡ –‹˜‹–›‹–Š‡—–ƒ– Šƒ‡ŽǡŽ‡ƒ†Ǧ ‹‰–‘ƒΪ‹ˆŽ—š‹–‘–Š‡ ‡ŽŽͳͻ͹ǡ͵ͳʹǡ͵ͳ͵ȋ ‹‰—”‡ͷȌǤ ‘”–Š‡E145Q —–ƒ–‹‘ǡin vitro •–—†‹‡•Šƒ˜‡•Š‘™‹ ”‡ƒ•‡†‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•—†‡” ‘–”‘Ž ‘†‹–‹‘•‹—Ǧ –ƒ– ‡ŽŽ•ǡ’”‡•—ƒ„Ž›†—‡–‘ƒΪ‹ˆŽ—šǦ‡†‹ƒ–‡††‡’‘Žƒ”‹œƒ–‹‘ǡƒ•™‡ŽŽƒ•‹ ”‡ƒ•‡† CYP11B2ƒ†NR4A2ȋNURR1Ȍ‡š’”‡••‹‘ǤͳͶͷ—–ƒ– Šƒ‡Ž•™‡”‡‡‹–Š‡”•‡•‹Ǧ –‹˜‡–‘–‡”–‹ƒ’‹ǡƒ‹Š‹„‹–‘”‘ˆ‹” Šƒ‡Ž•ǡ‘”–‘˜‡”ƒ’ƒ‹Žǡ™Š‹ Š™ƒ•’”‡˜‹‘—•Ž› •Š‘™–‘‹Š‹„‹––Š‡ͳͷͺǡ ͳͷͳƒ†ͳ͸ͺ—–ƒ–‹‘•ʹͲ͵ǡ͵ͳ͵Ǥ

ƒ–‹‡–•™‹–ŠKCNJ5 G151Eƒ†Y152C—–ƒ–‹‘•—•—ƒŽŽ›’”‡•‡–™‹–Šƒ‹Ž†‡”’Š‡‘Ǧ –›’‡ƒ††‘‘–‡ ‡••ƒ”‹Ž›”‡“—‹”‡•—”‰‡”›ʹ͹ͻǡ͵Ͳͺǡ͵ͳͳǡ͵ͳͶȋƒ„Ž‡͵ȌǤ‘–ƒ„Ž›ǡ–Š‡ ͳͷͳ —–ƒ–‹‘™ƒ••Š‘™–‘ ƒ—•‡‘”‡•‡˜‡”‡ ‡ŽŽ—Žƒ”†‡’‘Žƒ”‹œƒ–‹‘ƒ†•–”‘‰‡”ƒΪ —””‡–•—’‘‘˜‡”‡š’”‡••‹‘in vitroǡ™Š‹ Š™ƒ•ƒ ‘’ƒ‹‡†„›‹ ”‡ƒ•‡† ‡ŽŽ—Žƒ” Ž‡–ŠƒŽ‹–›‹ ‘’ƒ”‹•‘–‘ ‡ŽŽ• ƒ””›‹‰–Š‡ ͳͷͳ—–ƒ–‹‘ǤŠ‡”‡ˆ‘”‡ǡ‹–Šƒ•„‡‡ •—‰‰‡•–‡† –Šƒ– –Š‡ ‹Ž†‡” ’Š‡‘–›’‡ ƒ‹ˆ‡•–‹‰ ‹ ’ƒ–‹‡–• ™‹–Š –Š‡•‡ —–ƒ–‹‘• ‹‰Š–„‡†—‡–‘Š‹‰ŠŽ‡–ŠƒŽ‹–›‘ˆ ‡ŽŽ•‡š’”‡••‹‰–Š‡—–ƒ– Šƒ‡Ž͵ͳͳǤŠ‡ͳͷʹ —–ƒ–‹‘ǡŠ‘™‡˜‡”ǡ•‡‡•–‘Šƒ˜‡‘Ž›ƒ•ƒŽŽ‡ˆˆ‡ –‘–Š‡ Šƒ‡Žǯ•ƒΪ ‘†— –ƒ ‡ǡ ™Š‹ Š™‘—Ž†‡š’Žƒ‹–Š‡‹Ž†’Š‡‘–›’‡–Š‡’ƒ–‹‡–•’”‡•‡–™‹–ŠǤIn vitro•–—†‹‡•ƒŽ•‘ •Š‘™‹ ”‡ƒ•‡†‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•‹ ‡ŽŽ•Šƒ”„‘”‹‰–Š‡ͳͷʹ—–ƒ–‹‘ǡ„—––Š‡›

Ͷʹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ƒ”‡•—„•–ƒ–‹ƒŽŽ›Ž‘™‡”–Šƒˆ‘” ͳͷͳ—–ƒ– Šƒ‡Ž•ǤŠ‡•‡‹˜‡•–‹‰ƒ–‹‘•ƒŽ•‘ ‘Ǧ ˆ‹”‹ ”‡ƒ•‡†CYP11B2‡š’”‡••‹‘–Šƒ– ƒ„‡”‡†— ‡†„›–Š‡ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡” ‹ˆ‡†‹’‹‡͵ͳͶǤ

‘–ƒŽŽ   ƒ•‡•ˆ‘ŽŽ‘™–Š‡’ƒ––‡”•†‡• ”‹„‡†ƒ„‘˜‡ǣ‡‡š ‡’–‹‘ˆ”‘–Š‡•‡˜‡”‡  ’Š‡‘–›’‡—•—ƒŽŽ› ƒ—•‡†„›–Š‡KCNJ5 G151R‰‡”Ž‹‡—–ƒ–‹‘‹•ƒ›‘—‰ˆ‡Ǧ ƒŽ‡ ƒ’ƒ‡•‡’ƒ–‹‡–Ǥ›ƒ‰‡ͳͳǡŠ‡”Š›’‡”–‡•‹‘Šƒ†„‡‡•— ‡••ˆ—ŽŽ›ƒƒ‰‡†„› •’‹”‘‘Žƒ –‘‡ƒ†ƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ™ƒ•‘–†‡–‡ –‡†͵ͳͷǤ‡ ‡–Ž›ǡ–Š‡ˆ‹”•–   ƒ•‡™‹–Šƒ ‘„‹ƒ–‹‘‘ˆƒ†—•Š‹‰ǯ••›†”‘‡™ƒ•”‡’‘”–‡†‹ƒ›‘—‰Š‹Ǧ ‡•‡ƒ™‹–Šƒ‰‡”Ž‹‡KCNJ5 E145Q—–ƒ–‹‘Ǥ ‡•—ˆˆ‡”‡†ˆ”‘‡ƒ”Ž›Ǧ‘•‡–Š›’‡”Ǧ –‡•‹‘ǡƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒƒ†•–ƒ”–‡†–‘†‡˜‡Ž‘’—•Š‹‰ǯ••›†”‘‡‹Š‹•–™‡Ǧ –‹‡•Ǥ—•Š‹‰ǯ••›†”‘‡‹• Šƒ”ƒ –‡”‹œ‡†„›Š‹‰Š ‘”–‹•‘ŽŽ‡˜‡Ž•ǡ ƒ—•‹‰•›’–‘• •— Šƒ•Š›’‡”–‡•‹‘ǡƒ„†‘‹ƒŽ‘„‡•‹–›ǡƒ”‘—†ˆƒ ‡ƒ†•–”‹ƒ‡Ǥˆ–‡”„‹Žƒ–‡”ƒŽƒ†”‡Ǧ ƒŽ‡ –‘›ǡŠ‹•Š‡ƒŽ–Š‹’”‘˜‡†ƒ†‹˜‡•–‹‰ƒ–‹‘‘ˆŠ‹•ƒ†”‡ƒŽ–‹••—‡•—‰‰‡•–‡†–Šƒ– –Š‡‡š ‡•• ‘”–‹•‘Ž™ƒ• ƒ—•‡†„›ƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ͵ͳ͸Ǥ‘Ǧ•‡ ”‡–‹‘‘ˆƒŽ†‘•–‡”‘‡ ƒ† ‘”–‹•‘Ž‹•ƒ‡•–ƒ„Ž‹•Š‡†’Š‡‘‡‘‹’ƒ–‹‡–•™‹–Š–—‘”• ƒ””›‹‰ KCNJ5—Ǧ –ƒ–‹‘•͵ͳ͹ǡ͵ͳͺǤ

ƒ††‹–‹‘ǡƒ—”ƒet al.Šƒ˜‡”‡ ‡–Ž›†‡• ”‹„‡†ƒ ƒ•‡‘ˆ‡ƒ”Ž›Ǧ‘•‡– ƒ†„‹Žƒ–Ǧ ‡”ƒŽƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒǡ‹™Š‹ ŠŠ›’‡”’Žƒ•–‹ Ž‡•‹‘•†‹•’Žƒ›‡†ƒKCNJ5 G151R—–ƒǦ –‹‘ǤŠ‹•’Š‡‘–›’‡™ƒ•‘•–Ž‹‡Ž›–Š‡’”‘†— –‘ˆ‰‡‡–‹ ‘•ƒ‹ ‹•ǡ™‹–Š–Š‡—–ƒǦ –‹‘ ‘ —””‹‰ ‹ ƒ ƒ†”‡ƒŽ ’”‡ —”•‘” ‡•‘†‡”ƒŽ ‡ŽŽ ƒ† „‡‹‰ ’ƒ••‡† ‘ –‘ ‹–• †ƒ—‰Š–‡” ‡ŽŽ•͵ͳͻǤ‘–ƒ„Ž›ǡ–Š‡•‡ˆ‹†‹‰••—’’‘”––Š‡’”‡˜‹‘—•Ž›•—‰‰‡•–‡†’”‘Ž‹ˆ‡”ƒǦ –‹˜‡‡ˆˆ‡ –•‘ˆ–Š‡KCNJ5 G151R—–ƒ–‹‘ȋ ‘’ƒ”‡ͳͻ͹ǡʹͺͺǡ ‹‰—”‡ͷƒ†•‡ –‹‘ͺǤʹǤͳȌǤ

6.3.2.2.4Primary hyperaldosteronism with seizures and neurologic abnormali- ties – germline CACNA1D mutations De novo—–ƒ–‹‘•‹CACNA1DŠƒ˜‡„‡‡†‹• ‘˜‡”‡†‹–™‘ ƒ•‡•‘ˆ‡ƒ”Ž›Ǧ‘•‡–Š›Ǧ ’‡”–‡•‹‘ͳʹͳȋƒ„Ž‡͵ȌǤ‡•‹†‡•Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ†Š›’‘ƒŽ‡‹ƒǡ–Š‡•‡’ƒ–‹‡–• ƒŽ•‘•Š‘™‡†ƒ•‡˜‡”‡‡—”‘Ž‘‰‹ ƒŽ’Š‡‘–›’‡ǡ„‘–Š•—ˆˆ‡”‹‰ˆ”‘•‡‹œ—”‡•ƒ† ‡”‡Ǧ „”ƒŽ’ƒŽ•›Ǥ‘”‡‘˜‡”ǡ‘‡‘ˆ–Š‡’ƒ–‹‡–•†‹•’Žƒ›‡† ‘‰‡‹–ƒŽŠ‡ƒ”–ƒ‘ƒŽ›ǡ‹ Ž—†‹‰ ƒ˜‡–”‹ —Žƒ”•‡’–ƒŽ†‡ˆ‡ –ƒ–„‹”–ŠǤ—‡–‘–Š‡™‹†‡•’‡ –”—‘ˆ•›’–‘•™‹–Š•‡˜‡”‡ ‡—”‘Ž‘‰‹ ƒŽ‹’ƒ –•ǡ–Š‹•ˆ‘”‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•‹•”‡ˆ‡””‡†–‘ƒ•’”‹Ǧ ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•™‹–Š•‡‹œ—”‡•ƒ†‡—”‘Ž‘‰‹ ƒ„‘”ƒŽ‹–‹‡•ȋȌͳʹͳǡʹ͹ͻǤ ‘™‡˜‡”ǡ‹–‹••‘‡–‹‡•‹ Ž—†‡†‹–Š‡ ƒ–‡‰‘”›‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•–›’‡ ȋ  Ȍ–‘‰‡–Š‡”™‹–Š—–ƒ–‹‘•‹CACNA1H ȋˆ—”–Š‡” ‡Ž— ‹†ƒ–‡† ‹ •‡ –‹‘

Ͷ͵ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ͸Ǥ͵ǤʹǤʹǤͷȌʹͶͳǤŠ‡Ž‘ ƒ–‹‘•‘ˆ–Š‡—–ƒ–‹‘•ˆ‘—†‹–Š‡•‡–™‘’ƒ–‹‡–•ƒ– Š•‘ƒ–‹  ‘‡•ˆ‘—†‹•ȋ ͶͲ͵ǡ ͹ͷͲȌƒ†Ž‹‡‹”‡‰‹‘•‹˜‘Ž˜‡†‹ˆ‘”ƒ–‹‘‘ˆ–Š‡ Šƒ‡Ž’‘”‡ȋ ‘’ƒ”‡ ‹‰—”‡͸ȌǤ‘–Š•Š‘™ƒ –‹˜ƒ–‹‘ƒ–‘”‡Š›’‡”’‘Žƒ”‹œ‡†’‘Ǧ –‡–‹ƒŽ•ǡƒ†ǡŽ‹‡ ͶͲ͵ǡ ͶͲ͵ƒŽ•‘Ž‡ƒ†•–‘†‡ ”‡ƒ•‡† Šƒ‡Ž‹ƒ –‹˜ƒ–‹‘ͳʹͳǤŠ—•ǡ –Š‡•—‰‰‡•–‡†’ƒ–Š‘‡ Šƒ‹•‹••‹‹Žƒ”–‘–Š‡‘‡•—‰‰‡•–‡†ˆ‘”•‘ƒ–‹ CACNA1D —–ƒ–‹‘•ǣ  ”‡ƒ•‡†ƒʹΪ‹ˆŽ—š†—‡–‘ƒ –‹˜ƒ–‹‘ƒ–Ž‡••†‡’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•Ž‡ƒ†• –‘‹ ”‡ƒ•‡†ƒŽ†‘•–‡”‘‡•‡ ”‡–‹‘ͳʹͳǡʹ͹ͻȋ ‹‰—”‡ͷȌǤ

de novo‘ —””‹‰‰‡”Ž‹‡ ͶͲ͵—–ƒ–‹‘™ƒ•”‡ ‡–Ž›†‡• ”‹„‡†‹ƒ Š‹Ž†™‹–Š Š›’‡”‹•—Ž‹ƒ‡‹ Š›’‘‰Ž› ƒ‡‹ƒǡŠ‡ƒ”–†‡ˆ‡ –•ǡƒš‹ƒŽŠ›’‘–‘‹ƒǡ•‡‹œ—”‡•ƒ††‡˜‡ŽǦ ‘’‡–ƒŽ†‡Žƒ›ǤŠ‡’ƒ–‹‡–ǯ•ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•™‹–Š‹–Š‡‘”ƒŽ”ƒ‰‡ǡ™Š‹Ž‡”‡‹ Ž‡˜‡Ž•™‡”‡‘–”‡’‘”–‡†͵ʹͲǤ –‡”‡•–‹‰Ž›ǡ–”ƒ•‹‡–Š›’‘‰Ž› ƒ‡‹ƒ™ƒ•ƒŽ•‘†‡• ”‹„‡† ‹–Š‡’ƒ–‹‡– ƒ””›‹‰–Š‡•ƒ‡—–ƒ–‹‘ǤŠ‡†‹ˆˆ‡”‡ ‡•‹–Š‡’Š‡‘–›’‡• †‹•’Žƒ›‡†„›–Š‡–™‘’ƒ–‹‡–•ƒ”‡ —””‡–Ž›‘–—†‡”•–‘‘†„—–‹‰Š–„‡‡š’Žƒ‹‡†„› ƒ††‹–‹‘ƒŽ‰‡‡–‹ ‘”‡˜‹”‘‡–ƒŽˆƒ –‘”•ͳʹͳǡ͵ʹͲǤ

ƒ††‹–‹‘ǡ‹‰‰‡”ƒet al.”‡ ‡–Ž›†‡• ”‹„‡†ƒde novoCACNA1D‰ƒ‹Ǧ‘ˆǦˆ— –‹‘—Ǧ –ƒ–‹‘ȋͶͲͳ Ȍ‹ƒ‹ˆƒ–’ƒ–‹‡–™‹–Šƒ—–‹••’‡ –”—†‹•‘”†‡”ǡ‡’‹Ž‡’•›ƒ†‰‡‡”Ǧ ƒŽ‹œ‡†•‡‹œ—”‡•ǤŠ‡ƒ—–Š‘”•”‡ ‘‡† Ž‘•‡‘‹–‘”‹‰‘ˆ–Š‡’ƒ–‹‡–ˆ‘”‡‡”‰‹‰ •‹‰•‘ˆ’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•͵ʹͳǤ

‡•‹†‡•–Š‡ƒ†”‡ƒŽ‰Žƒ†ǡCACNA1D‹•ƒŽ•‘‡š’”‡••‡†‹–Š‡„”ƒ‹ǡŠ‡ƒ”–ƒ†’ƒ ”‡ƒ• ƒ ‘—–‹‰ˆ‘”–Š‡—Ž–‹•›•–‡‹ ƒ–—”‡‘ˆ–Š‡•›’–‘•ͳʹͳǡʹ͹ͻǡ͵ʹʹǡ͵ʹ͵Ǥ

6.3.2.2.5Familial hyperaldosteronism type IV - CACNA1H germline mutations ”‡ —””‡–‰‡”Ž‹‡—–ƒ–‹‘‹–Š‡‰‡‡CACNA1H™ƒ•”‡’‘”–‡†–‘ ƒ—•‡‡ƒ”Ž›Ǧ‘•‡– Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ†Š›’‡”–‡•‹‘„› Š‘ŽŽet al.‹ʹͲͳͷͳͳͺȋƒ„Ž‡͵ȌǤŠ‹••—„Ǧ ˆ‘”‘ˆˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘‹•‹•”‡ˆ‡””‡†–‘ƒ•  ȋ ‘’ƒ”‡‡Ǥ‰Ǥʹ͹ͻȌǤŠ‡Š‡–Ǧ ‡”‘œ›‰‘—•CACNA1H M1549V—–ƒ–‹‘™ƒ•†‹• ‘˜‡”‡†˜‹ƒ‡š‘‡•‡“—‡ ‹‰‹ƒ ‘Ǧ Š‘”–‘ˆͶͲ‹†‹˜‹†—ƒŽ•–Šƒ–™‡”‡†‹ƒ‰‘•‡†™‹–ŠŠ›’‡”–‡•‹‘„›ƒ‰‡ͳͲƒ†•Š‘™‡† Š‹‰ŠƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•™‹–Š•—’’”‡••‡†’Žƒ•ƒ”‡‹ƒ –‹˜‹–›Ǥ‘‡‘ˆ–Š‡’ƒ–‹‡–• ƒŽ•‘’”‡•‡–‡†™‹–ŠŠ›’‘ƒŽ‡‹ƒͳͳͺǤ —”–Š‡”‘”‡ǡ‘‡™ƒ•†‹ƒ‰‘•‡†™‹–Š†‡˜‡Ž‘’Ǧ ‡–ƒŽ†‡Žƒ›ƒ†‘‡™‹–Šƒ––‡–‹‘†‡ˆ‹ ‹–†‹•‘”†‡”Ǥ‡“—‡ ‹‰‘ˆˆƒ‹Ž›‡„‡”• •Š‘™‡†–Šƒ––Š‡—–ƒ–‹‘‘ —””‡†de novo‹•‘‡ ƒ•‡•ƒ†™ƒ•‹Š‡”‹–‡†ˆ”‘ƒ ’ƒ”‡–‹‘–Š‡”•Ǥ ‡‡ƒƒŽ›•‹•‘ˆ–Š‡ˆƒ‹Ž›‡„‡”••Š‘™‡†‹ ‘’Ž‡–‡’‡‡–”ƒ ‡ ˆ‘”–Š‡—–ƒ–‹‘ǡ™‹–Š–™‘‹†‹˜‹†—ƒŽ•„‡‹‰‘”‘–‡•‹˜‡†‡•’‹–‡„‡‹‰ ƒ””‹‡”•ǡŠ‹–Ǧ ‹‰ƒ–ƒ”‘Ž‡‘ˆŽ‹ˆ‡Ǧ•–›Ž‡ˆƒ –‘”•Ž‹‡•ƒŽ–Ǧ‹–ƒ‡‘”ƒ‰‡Ǧ†‡’‡†‡–ƒ –‹˜‹–›‘ˆ–Š‡

ͶͶ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ͳͳͺǤ —”–Š‡”‘”‡ǡ‘‡‘ˆ–Š‡‹†‡š ƒ•‡•ǯ‘–Š‡”•Ǧƒ—–ƒ–‹‘ ƒ””‹‡”Ǧ—†‡”™‡– ƒ†”‡ƒŽ‡ –‘›ˆ‘”•—•’‡ –‡†—‹Žƒ–‡”ƒŽ Ǥ ‡”ƒ†”‡ƒŽ‰Žƒ†•Š‘™‡†‹ ”‘• ‘’‹  Š›’‡”’Žƒ•‹ƒ‘ˆ–Š‡ ™‹–Š‘†—Ž‡•–Šƒ–‡š’”‡••‡†ͳ ͳͳͺǤ

ƒ††‹–‹‘ƒŽ ƒ•‡‘ˆ  ™‹–Šƒ†‹ˆˆ‡”‡–—–ƒ–‹‘‹–Š‡•ƒ‡ Ž‘ —•ǡ CACNA1H M1549Iǡ™ƒ•”‡ ‡–Ž›†‡• ”‹„‡†„›ƒ‹‹Žet al.ǣŠ‡Š‡–‡”‘œ›‰‘—•de novo—–ƒ–‹‘ ™ƒ•ˆ‘—†‹ƒ’ƒ–‹‡–™Š‘’”‡•‡–‡†™‹–Š’”‹ƒ”›ƒŽ†‘•–‡”‘‹•ƒ†Š›’‘ƒŽ‡‹ƒ ™Š‡–™‘‘–Š•‘Ž†Ǥ ’”‘˜‡‡–‘ˆŠ›’‡”–‡•‹‘ƒ†Š›’‘ƒŽ‡‹ƒ ‘—Ž† „‡ ƒ Š‹‡˜‡†„›•’‹”‘‘Žƒ –‘‡–”‡ƒ–‡–Ǥ”‡ƒ–‡– ‘—Ž†„‡†‹• ‘–‹—‡†ˆ‘”ƒ–‹‡‹ –Š‡’ƒ–‹‡–ǯ•‡ƒ”Ž›–‡‡•ǡ„—–‡‡†‡†–‘„‡”‡‹–”‘†— ‡†Žƒ–‡”†—‡–‘”‡‘ —””‡ ‡‘ˆ Š›’‡”–‡•‹‘Ǥ‘Š›’‡”’Žƒ•‹ƒ™ƒ•‹†‡–‹ˆ‹‡†‹ƒ• ƒǤŠ‡’ƒ–‹‡–™ƒ•ƒŽ•‘†‹ƒ‰Ǧ ‘•‡†™‹–Š—Ž–‹’Ž‡š†‡˜‡Ž‘’‡–ƒŽ†‹•‘”†‡”ͳͳͷǤ

ͳ ͳͷͶͻ—–ƒ–‹‘•ƒˆˆ‡ –•‡‰‡–͸‘ˆ†‘ƒ‹ ‘ˆ–Š‡’”‘–‡‹ǡƒ†–Š‡‡Ǧ –Š‹‘‹‡”‡•‹†—‡ƒ––Š‹•’‘•‹–‹‘‹•Š‹‰ŠŽ› ‘•‡”˜‡†ƒ ”‘•••’‡ ‹‡•ȋ ‘’ƒ”‡ ‹‰—”‡͸ ȌͳͳͺǤ –‹•ƒŽ•‘ ‘•‡”˜‡†ƒ ”‘••Ž‘™˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡†’ƒ”ƒŽ‘‰—‡•ǡ™Š‹Ž‡‹–‹••—„•–‹Ǧ –—–‡†™‹–Š‹•‘Ž‡— ‹‡‹Š‹‰Š˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Ž•Ǥ –Š‡Ž‘™˜‘Ž–ƒ‰‡Ǧ ‰ƒ–‡† ƒŽ ‹— Šƒ‡Žͳ ǡ–Š‡ ‘””‡•’‘†‹‰”‡•‹†—‡Šƒ•„‡‡•Š‘™–‘„‡’ƒ”– ‘ˆƒǦ Ǧ‘–‹˜‡–Šƒ–‹•‹˜‘Ž˜‡†‹˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž ‹ƒ –‹˜ƒǦ –‹‘ͳͳͺǡ͵ʹͶǡ͵ʹͷǤŽ‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡••Š‘™•Ž‘™‡”‹ƒ –‹˜ƒ–‹‘ƒ•™‡ŽŽƒ•ƒ –‹˜ƒǦ –‹‘ƒ–‘”‡Š›’‡”’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•ˆ‘”ͳ ͳͷͶͻ‹ ‘’ƒ”‹•‘–‘–Š‡ ™‹Ž†–›’‡ͳͳͺǤ‹‹Žƒ”ˆ‹†‹‰•Šƒ˜‡„‡‡”‡’‘”–‡†ˆ‘”–Š‡ͳͷͶͻ —–ƒ–‹‘Ǥƒ‹‹Žet al. ƒŽ•‘ •Š‘™ ƒ ‹ ”‡ƒ•‡† ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ƒ• ™‡ŽŽ ƒ• CYP11B2‡š’”‡••‹‘‹ ʹͻͷ ‡ŽŽ•™‹–Š–Š‡—–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ƒˆ–‡”•–‹—Žƒ–‹‘™‹–ŠΪ ”‡ˆͳͳͷǤ ‘”†‹‰Ž›ǡ–Š‡•—‰‰‡•–‡†’ƒ–Š‘‡ Šƒ‹•‹••‹‹Žƒ”–‘–Š‡‘‡’”‘’‘•‡†ˆ‘” ͳʹ͹ͻȋ ‘’ƒ”‡ ‹‰—”‡ͷȌǤ –Š‹•™‘”ǡ™‡ˆ—”–Š‡”‡Ž— ‹†ƒ–‡–Š‡‡ˆˆ‡ –•‘ˆ CACNA1H M1549V‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ƒin vitro•–—†›Ǥ

ƒ‹‹Žet al.ˆ—”–Š‡”‹’Ž‹ ƒ–‡‘–Š‡”‰‡”Ž‹‡—–ƒ–‹‘•‹CACNA1Hǡƒ‡Ž›S196L ƒ† P2083L, ‹’ƒ–‹‡–•†‹ƒ‰‘•‡†™‹–Š†—”‹‰ƒ†—Ž–Š‘‘†™‹–Šƒˆƒ‹Ž›Š‹•–‘”›‘ˆŠ›Ǧ ’‡”–‡•‹‘ǤŠ‡‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡•‘ˆ–Š‡•‡–™‘—–ƒ–‹‘•†‹ˆˆ‡”ƒ”‡†Ž› ˆ”‘–Š‘•‡ˆ‘—†‹‘†‹ˆ‹ ƒ–‹‘•‘ˆM1549 ™‹–Šƒ –‹˜ƒ–‹‘ƒ–•‹‹Žƒ”’‘–‡–‹ƒŽ•Ž‹‡ –Š‡™‹Ž†–›’‡ƒ†•ƒŽŽ†‹ˆˆ‡”‡ ‡•‹‹ƒ –‹˜ƒ–‹‘’ƒ ‡ǤŠ‡ʹͲͺ͵—–ƒ–‹‘•Š‘™‡† ƒ”‡†Ž›Ž‘™‡”™‹†‘™ —””‡–•–Šƒ–Š‡™‹Ž†–›’‡Ǥ ‘™‡˜‡”ǡ‹ ”‡ƒ•‡†ˆƒ ‹Ž‹–ƒ–‹‘ ™ƒ• ˆ‘—† ˆ‘” „‘–Š —–ƒ–‹‘•ͳͳͷǤ ƒ ‹Ž‹–ƒ–‹‘ †‡• ”‹„‡• ƒ ‹ ”‡ƒ•‡† —””‡– ‹ ”‡Ǧ •’‘•‡–‘–™‘ ‘•‡ —–‹˜‡’—Ž•‡•‹ ‘’ƒ”‹•‘–‘ƒ•‹‰Ž‡‘‡͵ʹ͸Ǥ  ”‡ƒ•‡†ƒŽ†‘•–‡Ǧ ”‘‡’”‘†— –‹‘ǡƒ•™‡ŽŽƒ•CYP11B2‡š’”‡••‹‘™ƒ•ˆ‘—†‹ ʹͻͷ ‡ŽŽ•™‹–Šͳͻ͸ Ͷͷ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ —–ƒ–‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ƒˆ–‡”Ϊ•–‹—Žƒ–‹‘ͳͳͷǤ —”–Š‡”‘”‡ǡ‹ƒ ‘Ǧ ˆ‡”‡ ‡ ‘–”‹„—–‹‘ǡ‘‘’et al.†‡• ”‹„‡ƒCACNA1H G1064R—–ƒ–‹‘‹ƒˆƒ‹Ž› ™‹–ŠŽƒ–‡Ǧ‘•‡– Ǥ  ʹͻͷ ‡ŽŽ•ǡ–Š‹•—–ƒ–‹‘ ƒ—•‡†‹ ”‡ƒ•‡†ƒŽ†‘•–‡”‘‡’”‘Ǧ †— –‹‘ƒ† CYP11B2‡š’”‡••‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ƒˆ–‡”Ϊ•–‹—Žƒ–‹‘Ǥ Ž–Š‘—‰Š–Š‡ƒ—–Š‘”• ‘ Ž—†‡–Šƒ––Š‡‹”ƒʹΪ•‹‰ƒŽ‹‰•–—†‹‡•‹  ‡ŽŽ•ƒ”‡‹†‹ ƒǦ –‹˜‡‘ˆ‹ ”‡ƒ•‡†ƒʹΪ‹ˆŽ—š–Š”‘—‰Š–Š‡—–ƒ– Šƒ‡Ž•ǡ‘†‹ˆˆ‡”‡ ‡•„‡–™‡‡™‹Ž† –›’‡ƒ†—–ƒ–™‡”‡ˆ‘—†‹‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡•‘ˆ–Š‡—–ƒ–‹‘͵ʹ͹Ǥ

‘–Š‡”CACNA1H‰‡”Ž‹‡—–ƒ–‹‘ȋͳͻͷͳȌ™ƒ•ˆ‘—†‹ƒ’ƒ–‹‡–’”‡•‡–‹‰™‹–Š ™‹–Š‘•‘ƒ–‹ —–ƒ–‹‘•‹–Š‡‹’Ž‹ ƒ–‡†‰‡‡•ƒ†™Š‘™ƒ• ‘’Ž‡–‡Ž› —”‡† ƒˆ–‡”ƒ†”‡ƒŽ‡ –‘›ǡ™Š‹ Š•—‰‰‡•–•–Šƒ––Š‡–—‘”™ƒ•–Š‡ƒ –—ƒŽ—†‡”Ž›‹‰ ƒ—•‡‘ˆ  Ǥ Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ •–—†‹‡• •Š‘™‡† ‹ ”‡ƒ•‡† Šƒ‡Ž ˆƒ ‹Ž‹–ƒ–‹‘Ǥ  ʹͻͷ ‡ŽŽ•™‹–Š–Š‹•—–ƒ–‹‘ǡCYP11B2‡š’”‡••‹‘™ƒ•‹ ”‡ƒ•‡†ƒˆ–‡”•–‹—Žƒ–‹‘™‹–ŠΪ ‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ǤŠ‡ƒ—–Š‘”••—‰‰‡•––Šƒ–—–ƒ–‹‘•‹CACNA1H‹‰Š– ƒŽ•‘ƒ –ƒ•ƒDz†”‹˜‡”dz‹–Š‡ˆ‘”ƒ–‹‘‘ˆͳͳͷǤ‘•—ƒ”‹œ‡ǡ—–ƒ–‹‘•‹‘–Š‡” ͳ ”‡•‹†—‡•„‡•‹†‡•ͳͷͶͻŠƒ˜‡„‡‡‹’Ž‹ ƒ–‡†‹ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡”‘Ǧ ‹•ǡ„—––Š‡‡˜‹†‡ ‡ˆ‘”–Š‡–‘„‡†‹•‡ƒ•‡Ǧ ƒ—•‹‰‹•”ƒ–Š‡”‹ ‘ Ž—•‹˜‡Ǥ’”‡•—‡† ”‘Ž‡‹ˆ‘”ƒ–‹‘”‡ƒ‹•–‘„‡‡•–ƒ„Ž‹•Š‡†„›ˆ—”–Š‡”•–—†‹‡•Ǥ

–Š‹•™‘”ǡ™‡’‡”ˆ‘”‡†ƒin vitroƒƒŽ›•‹•‘ˆƒ‘–Š‡”‰‡”Ž‹‡CACNA1H—–ƒ–‹‘ Ž‘ ƒ–‡†‹–Š‡˜‹ ‹‹–›‘ˆ–Š‡‘‡†‡• ”‹„‡†„›‘‘’et al.͵ʹ͹Ǥ –™ƒ•ˆ‘—†‹‘‘œ›Ǧ ‰‘–‹ –™‹•™‹–Šƒˆƒ‹Ž›Š‹•–‘”›‘ˆŠ›’‡”–‡•‹‘ǤŠ‡•ƒ‡’ƒ–‹‡–•ƒŽ•‘ ƒ””‹‡†—Ǧ –ƒ–‹‘•‹armadillo repeat-containing 5ȋARMC5Ȍƒ†DACH1ȋ•‡‡•‡ –‹‘͸ǤͳǤʹǤʹǤͳƒ† ͸Ǥ͵ǤʹǤʹǤ͸ȌǤ

6.3.2.2.6Putative roles of ARMC5 in familial hyperaldosteronism –Š‡’ƒ•–ǡ—–ƒ–‹‘•‹–Š‡’—–ƒ–‹˜‡–—‘”•—’’”‡••‘”‰‡‡armadillo repeat-contain- ing 5ȋARMC5ȌŠƒ˜‡„‡‡ˆ‘—†‹’ƒ–‹‡–•™‹–Šƒ ”‘‘†—Žƒ”ƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ ™‹–Š—•Š‹‰ǯ••›†”‘‡Ǥ –Š‡•‡’ƒ–‹‡–•ǡ‰‡”Ž‹‡—–ƒ–‹‘•ƒ”‡ƒ ‘’ƒ‹‡†„›ƒ •‘ƒ–‹ Dz•‡ ‘†Š‹–dz—–ƒ–‹‘‹–Š‡‘†—Ž‡ǤŠ‡•—‰‰‡•–‡†’ƒ–Š‘‡ Šƒ‹•‹•–Šƒ– ‹ƒ –‹˜ƒ–‹‰ͷ—–ƒ–‹‘•Ž‡ƒ†–‘†‡ ”‡ƒ•‡†ƒ’‘’–‘•‹•ƒ†–Š—•‹ ”‡ƒ•‡†•–‡”‘‹† •‡ ”‡–‹‘†—‡–‘‹ ”‡ƒ•‡† ‡ŽŽƒ••͵ʹͺǤ

‡ ‡–Ž›ǡŠ‡–‡”‘œ›‰‘—•‰‡”Ž‹‡—–ƒ–‹‘•‹ARMC5 Šƒ˜‡ƒŽ•‘„‡‡‹’Ž‹ ƒ–‡†‹’”‹Ǧ ƒ”›ƒŽ†‘•–‡”‘‹•Ǥ ‘‡•–—†›ǡ—–ƒ–‹‘•™‡”‡ˆ‘—†‹̱͵ͻΨ‘ˆ’ƒ–‹‡–•ǡ™Š‹Ž‡ ƒŽ–‡”ƒ–‹‘•‹̱ͳͲǤ͹Ψ‘ˆ–Š‡’ƒ–‹‡–•™‡”‡’”‡†‹ –‡†–‘„‡†ƒƒ‰‹‰in silicoǤ‘‡˜‹Ǧ

Ͷ͸ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ †‡ ‡‘ˆƒ•‘ƒ–‹ Dz•‡ ‘†Š‹–dz™ƒ•’”‡•‡–‹–Š‡ƒƒŽ›œ‡†•ƒ’Ž‡•͵ʹͻǤŽŽ‘ˆ–Š‡’ƒǦ –‹‡–•™‹–Š’—–ƒ–‹˜‡Ž›†ƒƒ‰‹‰—–ƒ–‹‘•™‡”‡ˆ”‹ ƒ‡”‹ ƒ•ǡƒ‰”‘—’™‹–Šƒ ‹ ”‡ƒ•‡†„—”†‡‘ˆ”ƒ”‡˜ƒ”‹ƒ–•ʹ͹ͻǡ͵͵ͲǤ‘–Š‡”•–—†›ǡ™Š‹ Š‹˜‡•–‹‰ƒ–‡†ARMC5—Ǧ –ƒ–‹‘•‹‘•–Ž›ƒ— ƒ•‹ƒ’ƒ–‹‡–•™‹–Šǡ‹†‡–‹ˆ‹‡†•‡“—‡ ‡˜ƒ”‹ƒ–‹‘‹ͳͺ‘—–‘ˆ ͵ͻ’ƒ–‹‡–•ǡ‘‡‘ˆ™Š‹ Š™‡”‡’”‡†‹ –‡†–‘ƒŽ–‡”’”‘–‡‹ˆ— –‹‘in silico͵͵ͳǤ ‡ ‡ǡ †‡•’‹–‡•‘‡‹†‹ ƒ–‹‘•ǡ–Š‡‡šƒ –”‘Ž‡‘ˆARMC5—–ƒ–‹‘•‹ˆƒ‹Ž‹ƒŽŠ›’‡”ƒŽ†‘•–‡Ǧ ”‘‹•”‡ƒ‹•— Ž‡ƒ”ʹ͹ͻǡ͵͵ͳǤ

6.3.2.3 Cell lines as models for primary hyperaldosteronism Ž–Š‘—‰Š‘˜‡”–‹‡ƒ›†‹ˆˆ‡”‡–ƒ’’”‘ƒ Š‡•Šƒ˜‡„‡‡—•‡†–‘‹˜‡•–‹‰ƒ–‡ƒ†”‡‘Ǧ ‘”–‹ ƒŽ„‡Šƒ˜‹‘”in vitroǡ‡•–ƒ„Ž‹•Š‡†•–‡”‘‹†‘‰‡‹  ‡ŽŽŽ‹‡•Šƒ˜‡–Š‡‹’‘”–ƒ–ƒ†Ǧ ˜ƒ–ƒ‰‡–Šƒ––Š‡› ƒ’”‘˜‹†‡–Š‡”‡•‡ƒ” Š‡”™‹–ŠŽƒ”‰‡—„‡”•‘ˆ”‡ƒ†‹Ž›ƒ˜ƒ‹Žƒ„Ž‡ ˆ— –‹‘ƒŽ•–‡”‘‹†‘‰‡‹  ‡ŽŽ•͵͵ʹǤ

‡•’‹–‡–Š‡‡š‹•–‡ ‡‘ˆƒ˜ƒ”‹‡–›‘ˆŠ—ƒƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽŽ‹‡•ǡ•‡˜‡”ƒŽˆƒ‹Ž–‘’”‘Ǧ †— ‡•–‡”‘‹†•ƒ†ƒ”‡–Š‡”‡ˆ‘”‡‘ˆŽ‹‹–‡†—•‡‹–Š‡‹˜‡•–‹‰ƒ–‹‘‘ˆȋ ‘’ƒ”‡͵͵ʹȂ ͵͵͸ȌǤ‡’”‘‹‡–‡š ‡’–‹‘‹•–Š‡Š—ƒ ‡ŽŽŽ‹‡ ʹͻͷƒ†‹–•†‡”‹˜ƒ–‹˜‡•ǡ™Š‹ Š ‘”‹‰‹ƒ–‡†ˆ”‘ƒ–—‘”‹ƒͶͺ›‡ƒ”‘Ž†ˆ‡ƒŽ‡’ƒ–‹‡–’”‡•‡–‹‰ƒ‘‰•–‘–Š‡”•™‹–Š Š‹‰Š—”‹ƒ”›Ž‡˜‡Ž•‘ˆƒŽ†‘•–‡”‘‡ƒ† ‘”–‹•‘Žƒ•™‡ŽŽƒ••›’–‘•‘ˆ˜‹”‹Ž‹œƒ–‹‘͵͵͹Ǥ Š‡‘”‹‰‹ƒŽ ‡ŽŽ•ǡ‰”‘™‹‰‹‘Ž›•Ž‹‰Š–Ž›•—”ˆƒ ‡Ǧƒ––ƒ Š‡† Ž—•–‡”•ǡ™‡”‡•‡Ž‡ –‡†ˆ‘” ƒ†Š‡”‡ ‡ǡ™Š‹ Š›‹‡Ž†‡†–Š‡ ʹͻͷ ‡ŽŽŽ‹‡Ǥ—„•–”ƒ‹•‘ˆ–Š‡•‡ ‡ŽŽ•ǡ‘’–‹‹œ‡†ˆ‘” ‰”‘™–Š‹†‹ˆˆ‡”‡–‡†‹ƒǡ™‡”‡•‡Ž‡ –‡†͵͵ʹǡ͵͵ͺǤ ͳͷ ‡ŽŽ•ƒ”‡‘‘ Ž‘ƒŽ ʹͻͷǦ†‡Ǧ ”‹˜‡† ‡ŽŽ•Ǥ”‹‰‹ƒŽŽ›‰‡‡”ƒ–‡†™‹–Š–Š‡ƒ‹–‘ ”‡ƒ–‡ƒ‘˜‡Ž•–‡”‘‹†Ǧ’”‘†— ‹‰ƒ†Ǧ ”‡ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡†‡”‹˜‡†ˆ”‘ƒ†‹ˆˆ‡”‡–’ƒ–‹‡–ǡ–Š‡›™‡”‡Žƒ–‡”‹†‡–‹ˆ‹‡†–‘ „‡†‡”‹˜‡†ˆ”‘ ‘–ƒ‹ƒ–‹‰ ʹͻͷ ‡ŽŽ•͵͵͵ǡ͵͵ͻǤ

‹‹Žƒ”–‘–Š‡–—‘”–Š‡›‘”‹‰‹ƒ–‡†ˆ”‘ǡ ʹͻͷǦ†‡”‹˜‡† ‡ŽŽ•’”‘†— ‡•–‡”‘‹†•ƒ† ‡š’”‡••‰‡‡• ‘†‹‰ˆ‘”•–‡”‘‹†‘‰‡‹ ‡œ›‡•–Šƒ–‘”‹‰‹ƒ–‡ˆ”‘†‹ˆˆ‡”‡–œ‘‡•‘ˆ –Š‡Š‡ƒŽ–Š›ƒ†”‡ƒŽ‰Žƒ†ȋ ‘’ƒ”‡‡Ǥ‰Ǥ ͵͵ʹǡ͵͵͹ǡ͵͵ͻȂ͵Ͷ͵ȌǤš’”‡••‹‘‘ˆ–Š‡ƒŽ†‘•–‡”‘‡ •›–Šƒ•‡CYP11B2ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡•‡ ‡ŽŽ• ƒ„‡•–‹—Žƒ–‡†™‹–Š ‰ ƒ†Ϊ”‡ˆ͹ʹǡ͵͵ͻǡ͵Ͷʹǡ͵Ͷ͵Ǥ ‘™‡˜‡”ǡ–Š‡˜ƒ”‹‘—• ʹͻͷǦ†‡”‹˜‡† ‡ŽŽŽ‹‡•ƒ†•—„•–”ƒ‹• †‹ˆˆ‡”ƒ”‡†Ž›‹–Š‡‹” ƒ’ƒ ‹–›–‘’”‘†— ‡ƒŽ†‘•–‡”‘‡ƒ†–‘‡š’”‡••CYP11B2͵ͶͶǤ Ž†‘•–‡”‘‡’”‘†— –‹‘‹‰Š–ˆ—”–Š‡”„‡‹ˆŽ—‡ ‡†„›‘†‹ˆ‹ ƒ–‹‘•‘ˆ —Ž–—”‡ ‘†‹Ǧ –‹‘•͵ͶͷǤ

ͳͷƒ† ʹͻͷ ‡ŽŽ• ‘•–‹–—–‡ƒ™‡ŽŽǦ‡•–ƒ„Ž‹•Š‡† ‡ŽŽ —Ž–—”‡‘†‡Žˆ‘” ǤŠ‡› Šƒ˜‡„‡‡–”ƒ•ˆ‡ –‡†—•‹‰ƒ˜ƒ”‹‡–›‘ˆ‡–Š‘†•ǡ•–ƒ„Ž‡ ‡ŽŽŽ‹‡•Šƒ˜‡„‡‡‰‡‡”ƒ–‡†ǡ

Ͷ͹ ϲ/ŶƚƌŽĚƵĐƚŝŽŶ ‡ŽŽ —Ž–—”‡ •—’‡”ƒ–ƒ–• Šƒ˜‡ „‡‡ƒ••‡••‡†ˆ‘”•–‡”‘‹† ‘–‡– ƒ† ‡š’”‡••‹‘ ‘ˆ •–‡”‘‹†‘‰‡‹ ‡œ›‡•Šƒ•„‡‡‘‹–‘”‡†‹—‡”‘—••–—†‹‡•–‘‹˜‡•–‹‰ƒ–‡–Š‡—Ǧ †‡”Ž›‹‰‡ˆˆ‡ –•‹Š›’‡”ƒŽ†‘•–‡”‘‹•ȋ ‘’ƒ”‡‡Ǥ‰ǤͳͳͷǡʹͲ͵ǡʹͷͲǡ͵Ͳͻǡ͵ͳͲȌǤ‘•–‹’‘”–ƒ–Ž› ˆ‘”–Š‹•™‘”ǡ–Š‡›Šƒ˜‡„‡‡—•‡†„›—Ž–‹’Ž‡•–—†‹‡•–‘‹˜‡•–‹‰ƒ–‡–Š‡”‘Ž‡‘ˆKCNJ5 ƒ†˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž—–ƒ–‹‘•‹ ȋ‡Ǥ‰ǤͳͳͷǡʹͷͲǡʹ͸ͺǡ͵ͲͻȌǤŠ‡in vitro‡šǦ ’‡”‹‡–•ˆ‡ƒ–—”‡†‹–Š‹•™‘”™‹ŽŽ”‡Ž›‘ ͳͷƒ† ʹͻͷ ‡ŽŽ•ƒ•‘†‡Ž•ˆ‘”  ‹˜‘Ž˜‹‰‹‘ Šƒ‡Ž—–ƒ–‹‘•Ǥ





Ͷͺ Ȁͺ Ȁͳ Ȁͺ ‰ ‹ ‹  ƒ–‹‡–•™‹–Š ƒ†”‡ƒŽ‡ –‘› ȋšȀ–‘–ƒŽȌ ƒŽ•‘”‡’‘”–‡†‹ƒ  ƒ ͳȀʹ Š ǡͳȀ ǡͳ ͲȀͳǡͳȀ ͘ Š Š ––‘‰”‡ƒ–‡•–ǡ Ȁ͹ȋͳȀȌ ʹ Ϯϳϵ ‰ •’‘†‹‰–‘ ‡†‹ ƒ–‹‘ ȋšȀ–‘–ƒŽȌ ƒ–‹‡–•‘–”‡Ǧ ‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ†ƒ–ƒȋƒ –‹˜ƒ–‹‘Ȁ‹ƒ –‹˜ƒ–‹‘

ǡ ͵ʹͲ ‡šƒ –—„‡”‘ˆ•‡“—‡ ‡†ˆƒ‹Ž›‡„‡”•ȋ‹ Ž—†‹‰ —‹Žƒ–‡”ƒŽƒ†”‡ƒŽ‡ –‘›ǡ‘Ǧ —”‹‰ ‡ ‹ Ȁʹ ͲȀͳ ˆ ͶȀ ͶȀ ͶȀ ƒ–‹‡–•™‹–Š ƒ ”‘• ‘’‹  Š›’‡”’Žƒ•‹ƒ ȋšȀ–‘–ƒŽȌ ‡Ž‘’‡–ƒŽ†‡Žƒ› ĚĂƉƚĞĚĨƌŽŵ<ŽƌĂŚĂŶĚ^ĐŚŽůů͕ϮϬϭϱ ”‡•‹•–ƒ–Š›’‡”–‡•‹‘ǡ Š ȋŽƒ–‡Ǧ‘•‡–Ȍ ‡†‹ƒƒ‰‡ ƒ–†‹ƒ‰‘•‹• ȋ›‡ƒ”•Ȍ ͶȀ ‡  ͹Ǥͷ ͲȀ͸ȋʹȀȌ ͲȀͺ ͳ † ʹ ʹ ʹȀʹ ʹȀʹ ʹȀʹ ʹ ͶǤͷ ʹȀʹ ʹȀʹ ʹȀʹ ͷ ͳ ʹȀͶȋͳȀȌ ͵ȀͶȋͳȀȌ ͵ȀͶȋͳȀȌ ͺ ͵ ͲȀ͹ȋͳȀȌ ͳ —„‡” ‘ˆ•—„Œ‡ –• ‡š Ž—†‹‰–™‘ƒ†—Ž–‘”‘–‡•‹˜‡ ƒ””‹‡”•ǡ † ‘ˆ–Š‡–™‘‹††Ž‡˜ƒŽ—‡•ǡ™Š‡ƒŽŽ—„‡”•ƒ”‡Ž‹•–‡†•ƒŽŽ‡• ‘ǡ   ͳ Ͷͺ ͳȀͳ ͳȀͳ ͳ  ŝŶŐĞŶĞƐĞŶĐŽĚŝŶŐŝŽŶĐŚĂŶŶĞůƐ͘ ͵ͳ͵ ͵ͳͶ  Ͷƒˆˆ‡ –‡†  ͵Ͳͺ  ͺ ͳ ͳ Ͳ ͷ Ȁ ͲȀͳ ͲȀͳ ͲȀͳ ͲȀͳ ͲȀͳ ʹͶͶͳȀʹͲȀͳ  ͳ ʹ ͲǤʹ ͶͳǤͷ ͲȀͳ ͳ ͲȀͳ ͲȀͳ   ͵ʹ͹  ͵ ͷ ͵Ȁ͵ ͵Ȁ͵ ͵Ȁ͵ ͵ͳͷ ͵ͳͳ ͳʹͳ ͳʹͳ ͳͳͺ ͳͳͷ ͳͳͷ ͳͳͷ ͵ͳͳ ͵ͳ͸ ͳͻ͹  ͵ͳʹ ʹͲͳʹ †ƒ Š‹ǡʹͲͳͶ ‘‰ǡʹͲͳ͸ —Žƒ–‡”‘ǡʹͲͳʹ „‡ˆ‘”‡ƒ–‹‹‡”ƒŽ‘ ‘”–‹ ‘‹†•„‡ ƒ‡ƒ ‡••‹„Ž‡ǡ ‘‘’ǡʹͲͳ͸ ‰ ƒ‹‹ŽǡʹͲͳ͸

  Š‘ŽŽǡʹͲͳ͵ ƒ‹‹ŽǡʹͲͳ͸ „ ƒŽ•‘”‡’‘”–‡†‹ƒ’ƒ–‹‡–™‹–ŠŠ›’‘‰Ž› ƒ‡‹ƒǡ•‡‹œ—”‡•ƒ††‡˜

„ ǡ   Š‘ŽŽǡʹͲͳʹ ͵ͳͻ ƒ Ž‡ˆ–ƒ†”‡ƒŽǡ ˆ ͳ ͳͷͶͻ  ƒ‹‹ŽǡʹͲͳ͸ ͳ ʹͲͺ͵  ͷͳͷʹ ‘–‹ ‘‡ǡʹͲͳ͵  ͷ ͳͷͳ  Š‘ŽŽǡʹͲͳʹ  ͷͳͶͷ ‘–‹ ‘‡ǡʹͲͳͷ ͳ ͳͻ͸  ͷ ͳͷ͹ Šƒ”ƒ†ƒ”‹ǡ ͳ ͹ͷͲ  Š‘ŽŽǡʹͲͳ͵ ͳ  ͳͲ͸Ͷ  ͷ ͳͷͳ  ͳ ͶͲ͵    ͷͳͷͺ Š‘‹ǡʹͲͳͳ –›’‡ —–ƒ–‹‘ –—†› ‘–ƒŽ   ͳ ͳͷͶͻ  Š‘ŽŽǡʹͲͳͷ ’ƒ–‹‡–™‹–Š‰‡‡–‹ ‘•ƒ‹ ‹• ‘”‰‡‡”ƒŽȌ’‘‘”Ž›•—’’‘”– Ǧ ƒ—•‹‰’”‘’‡”–‹‡•‘ˆ–Š‡—–ƒ–‹ †‡ ‡ƒ•‡†Ȍ‘–•’‡ ‹ˆ‹‡†ǡ dĂďůĞϯ͘ŚĂƌĂĐƚĞƌŝƐƚŝĐƐŽĨ&,ƉĂƚŝĞŶƚƐǁŝƚŚŐĞƌŵůŝŶĞŵƵƚĂƚŝŽŶƐ Ȁǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ǡ‡†‹ƒˆ‘”‡˜‡˜ƒŽ—‡•‡š’”‡••‡†ƒ•–Š‡‡ƒ

Ͷͻ ϳWƌŽũĞĐƚƐ

7 Projects

7.1 Novelsomaticmutationsinprimaryhyperaldosteronismarerelatedtothe clinical,radiologicalandpathologicalphenotype

7.1.1 Objectivesofthework ‡ —””‡–•‘ƒ–‹ —–ƒ–‹‘•‹KCNJ5ǡCACNA1DǡATP1A1ǡATP2B3ƒ†CTNNB1Šƒ˜‡ „‡‡†‡• ”‹„‡†‹•ͳʹͳǡͳͻ͹ǡʹͶͶǡʹͶͷǤ‹ ”‡ƒ•‹‰—„‡”‘ˆ•–—†‹‡•Šƒ˜‡–”‹‡†–‘Ž‹ –Š‡—–ƒ–‹‘ƒŽ•–ƒ–—•‘ˆ–Š‡–—‘”–‘’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •ǡ‹’ƒ”–’”‘†— Ǧ ‹‰ ‘–”ƒ†‹ –‘”›”‡•—Ž–•ȋ ‘’ƒ”‡ƒ„Ž‡͸ǡƒ„Ž‡͹ǡƒ„Ž‡ͺǡƒ„Ž‡ͻȌǤŠ‡‰‘ƒŽ‘ˆ–Š‡ •–—†›ƒ–Šƒ†‹•–‘Ž‹—–ƒ–‹‘•ˆ‘—†‹•ˆ”‘–Š”‡‡†‹ˆˆ‡”‡– ‡–‡”•–‘ƒ ‘”Ǧ ”‡•’‘†‹‰ Ž‹‹ ƒŽǡ”ƒ†‹‘Ž‘‰‹ ƒŽƒ†’ƒ–Š‘Ž‘‰‹ ƒŽ’Š‡‘–›’‡ǤŠ‡”‡„›ǡ–Š‹••–—†›ƒ‹• ƒ–„”‘ƒ†‡‹‰‘—”—†‡”•–ƒ†‹‰‘ˆ–Š‡†‹•–‹ –‹‘•„‡–™‡‡†‹ˆˆ‡”‡–•—„–›’‡•Ǥ Š‹• ‘—Ž† ‘–”‹„—–‡ –‘ ˆƒ ‹Ž‹–ƒ–‹‘ ‹ –Š‡ †‹ƒ‰‘•‹• ‘ˆ  ƒ† –Š‡”‡ˆ‘”‡ ‹’”‘˜‡ ‡†‹ ƒŽ ƒ”‡ˆ‘”–Š‡ƒˆˆ‡ –‡†’ƒ–‹‡–‰”‘—’Ǥ



7.1.2 Manuscript Ǥ Ǥ Š‘ŽŽǡ ǤǤ ‡ƒŽ›ǡǤŠ‹‡ŽǡǤǤ ‘•‡ ƒǡǤǤ”‘™ǡ ǤǤ—•–ƒǡǤ Ǥ ‘”‡ǡ Ǥ‹‡–”‹ Šǡ Ǥ‹‡‡”ǡǤò òÚ›ŽòǡǤǤ‡‹‡”ǡǤǤ‡‹•ǡ Ǥ ‘Šǡ Ǥ”‹•–‹ƒ•‡ǡǤ ƒŠƒŒƒǡǤ‘”ƒŠǡǤǤ‹ˆ–‘ǡǤǤ”ƒ•ƒ†ǡƒ†Ǥƒ”Ž‹‰ǡDz‘˜‡Ž•‘ƒ–‹ —–ƒ–‹‘• ‹’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ”‡”‡Žƒ–‡†–‘–Š‡ Ž‹‹ ƒŽǡ”ƒ†‹‘Ž‘‰‹ ƒŽƒ†’ƒ–Š‘Ž‘‰‹ ƒŽ ’Š‡‘–›’‡ǡdzŽ‹‹ ƒŽ†‘ ”‹‘Ž‘‰›ǡ˜‘ŽǤͺ͵ǡ’’Ǥ͹͹ͻȂ͹ͺͻǡʹͲͳͷǤ

‘”ƒ†‡• ”‹’–‹‘‘ˆ–Š‡ ‘–”‹„—–‹‘•ƒ†‡–‘–Š‹•ƒ—• ”‹’–„›ǤǤ‡‹‡”’Ž‡ƒ•‡ ”‡ˆ‡”–‘•‡ –‹‘ͳͳǤͳǤͳ‹–Š‡ƒ’’‡†‹šǤ



Inaccordancewithregulations,publicationreprintswereremovedfromthisdissertaǦ tionforthefinalprintversion.



ͷͲ ϳWƌŽũĞĐƚƐ 7.2 MacrolidesselectivelyinhibitmutantKCNJ5potassiumchannelsthatcause aldosteroneǦproducingadenoma

7.2.1 Objectivesoftheproject ‘ƒ–‹ —–ƒ–‹‘•‹–Š‡’‘–ƒ••‹— Šƒ‡Ž ͷƒ”‡ˆ‘—†‹ƒ”‘—† ͶͲΨ ‘ˆ •ʹͶ͹Ǥ ͳͷͳƒ†ͳ͸ͺƒ”‡–Š‡‘•– ‘‘˜ƒ”‹ƒ–•„›ˆƒ”ǡ™Š‹Ž‡‘–Š‡”—–ƒǦ –‹‘•ƒ”‡”ƒ”‡ʹͶǡʹ͵͹ǤŠ‡•‡ƒŽ–‡”ƒ–‹‘•Šƒ˜‡„‡‡•Š‘™–‘‹ ”‡ƒ•‡ƒŽ†‘•–‡”‘‡’”‘†— Ǧ –‹‘‹ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽ•ʹͷͲǤŠ‡‰‘ƒŽ‘ˆ–Š‹•’”‘Œ‡ –™ƒ•–‘‹†‡–‹ˆ› ‘Ǧ ’‘—†•–Šƒ–„Ž‘  ͷ Šƒ‡Ž•™‹–Š ͳͷͳƒ†ͳ͸ͺ—–ƒ–‹‘•™‹–Š‘—–‹Š‹„‹–Ǧ ‹‰–Š‡™‹Ž†–›’‡Ǥ—„•–ƒ ‡•‡‡–‹‰–Š‡•‡ ”‹–‡”‹ƒ ‘—Ž†’‘–‡–‹ƒŽŽ›„‡—•‡†‹–Š‡ †‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘ˆ’ƒ–‹‡–•™‹–ŠKCNJ5—–ƒ–•ƒ†–Š—•‹’”‘˜‡‡†‹ ƒŽ ƒ”‡ˆ‘”–Š‹•‰”‘—’Ǥˆ–‡”• ”‡‡‹‰‘˜‡”͹͵ǡͲͲͲ•—„•–ƒ ‡•ǡ–Š‡‡ˆˆ‡ –•‘ˆ–Š‡‘•– ’”‘‹•‹‰ ‘’‘—† ‘ ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ƒ† CYP11B2‡š’”‡••‹‘™‡”‡ƒ•Ǧ •‡••‡†‹•–—†‹‡•‘ˆƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽ•‡š’”‡••‹‰—–ƒ– ͷǤ”‡†— Ǧ –‹‘‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘—’‘‹Š‹„‹–‘”–”‡ƒ–‡–™‘—Ž†„‡ƒˆ‹”•–‹†‹ ƒ–‘”–Šƒ– ƒ•‹‹Žƒ”‡ˆˆ‡ –‹‰Š–„‡ƒ Š‹‡˜‡†invivoǡ•—„•–ƒ–‹ƒ–‹‰–Š‡’‘–‡–‹ƒŽ„‡‡ˆ‹–•‘ˆ—Ǧ –ƒ– ͷ Šƒ‡Ž„Ž‘ ‡”•ˆ‘”’ƒ–‹‡–•Ǥ



7.2.2 Manuscript Ǥ Ǥ Š‘ŽŽǡǤ„”‹‘ŽƒǡǤŠƒ‰ǡǤǤ‡‹‡”ǡǤŽ—‡”ǡǤ Ǥƒœ‹‡” œƒǡ ǤŠƒ‰ǡ Ǥ ‘›‡”ǡ ǤǤ‡”‡ŽǡǤƒ‰ǡƒ†ǤǤ‹ˆ–‘ǡDzƒ ”‘Ž‹†‡••‡Ž‡ –‹˜‡Ž›‹Š‹„‹–—–ƒ–  ͷ’‘–ƒ••‹— Šƒ‡Ž•–Šƒ– ƒ—•‡ ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ƒ†‡‘ƒǡdz ‘—”ƒŽ‘ˆ Ž‹‹ ƒŽ ˜‡•–‹‰ƒ–‹‘ǡ˜‘ŽǤͳʹ͹ǡ‘Ǥ͹ǡ’’ǤͳȂͳʹǡʹͲͳ͹Ǥ

‘”ƒ†‡• ”‹’–‹‘‘ˆ–Š‡ ‘–”‹„—–‹‘•ƒ†‡–‘–Š‹•ƒ—• ”‹’–„›ǤǤ‡‹‡”’Ž‡ƒ•‡ ”‡ˆ‡”–‘•‡ –‹‘ͳͳǤͳǤʹ‹–Š‡ƒ’’‡†‹šǤ



Inaccordancewithregulations,publicationreprintswereremovedfromthisdissertaǦ tionforthefinalprintversion.







ͷͳ ϳWƌŽũĞĐƚƐ 7.3 CACNA1H M1549V mutant calcium channel causes autonomous aldosteǦ roneproductioninHAC15cellsandisinhibitedbymibefradil

7.3.1 Objectivesoftheproject Š‡‰‡”Ž‹‡CACNA1HM1549V˜ƒ”‹ƒ–™ƒ•ˆ‹”•–†‡• ”‹„‡†‹ƒ‰”‘—’‘ˆ’ƒ–‹‡–•™‹–Š ‡ƒ”Ž›Ǧ‘•‡–Š›’‡”ƒŽ†‘•–‡”‘‹•ǤŽ‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡••—‰‰‡•–‡†ƒ‰ƒ‹‘ˆˆ— Ǧ –‹‘‘ˆ–Š‡—–ƒ– Šƒ‡Ž•ǡ•Š‘™‹‰•Ž‘™‡”‹ƒ –‹˜ƒ–‹‘ƒ†ƒ –‹˜ƒ–‹‘ƒ–‘”‡Š›Ǧ ’‡”’‘Žƒ”‹œ‡†’‘–‡–‹ƒŽ•‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ͳͳͺǤŠ‡‰‘ƒŽ‘ˆ–Š‹•’”‘Œ‡ –™ƒ• –‘ˆ—”–Š‡”‡Ž— ‹†ƒ–‡–Š‡”‘Ž‡‘ˆ–Š‡—–ƒ–‹‘ƒ•ƒ ƒ—•‡‘ˆ  ǤŠ‡”‡ˆ‘”‡ǡ™‡‹˜‡•–‹Ǧ ‰ƒ–‡†–Š‡‡ˆˆ‡ –•‘ˆ–Š‡—–ƒ–‹‘‘CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǡ ™Š‹ Š‹‰Š–„‡‹†‹ ƒ–‹˜‡‘ˆ‹–•invivo‡ˆˆ‡ –•Ǥ ƒ ‘”†ƒ ‡™‹–Š’”‡˜‹‘—•”‡’‘”–•ǡƒ ‰ƒ‹Ǧ‘ˆǦˆ— –‹‘—–ƒ–‹‘ ƒ—•‹‰ ™ƒ•‡š’‡ –‡†–‘‹ ”‡ƒ•‡„‘–ŠCYP11B2‡š’”‡•Ǧ •‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽ•ȋ ‘’ƒ”‡‡Ǥ‰ǤʹͷͲǡ͵ͲͻȌǤ‘‘„–ƒ‹ ƒ‘˜‡”˜‹‡™‘˜‡”’‘–‡–‹ƒŽ‡ˆˆ‡ –•ǡ–Š‡‹’ƒ –‘ˆ–Š‡—–ƒ–‹‘™ƒ•ƒƒŽ›œ‡†—†‡”ƒ ™‹†‡”ƒ‰‡‘ˆ ‘†‹–‹‘•ȋ„ƒ•ƒŽǡ•–‹—Žƒ–‘”›ƒ†‹Š‹„‹–‘”›ȌǤŠ‡”‡„›ǡǦ–›’‡ Šƒ‡Ž ‹Š‹„‹–‹‘•‡”˜‡†–‘–™‘’—”’‘•‡•ǣ ‹”•–ǡ–‘ƒƒŽ›œ‡™Š‡–Š‡”ƒ›‘„•‡”˜‡†‡ˆˆ‡ –™ƒ• ‹†‡‡†–Š‡”‡•—Ž–‘ˆŽ‘™˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Žƒ –‹˜‹–›ƒ†•‡ ‘†ǡ–‘‡šǦ ’Ž‘”‡–Š‡’Šƒ”ƒ ‘Ž‘‰›‘ˆͳ ͳͷͶͻ Šƒ‡Ž•ǡ™Š‹ Š ‘—Ž†Ž‡ƒ†–‘‡™‹Ǧ ’—Ž•‡•ˆ‘”–Š‡–”‡ƒ–‡–‘ˆ  ’ƒ–‹‡–•Ǥ



7.3.2 Manuscript ǤǤ‡‹‡”ǡ ǤƒŽ‡†ƒǡǤ‡‹†‡Žǡƒ†Ǥ Ǥ Š‘ŽŽǡDzͳ ͳͷͶͻ—–ƒ– ƒŽ ‹— Šƒ‡Ž ƒ—•‡•ƒ—–‘‘‘—•ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ͳͷ ‡ŽŽ•ƒ†‹•‹Š‹„‹–‡†„› ‹„‡ˆ”ƒ†‹Žǡdz†‘ ”‹‘Ž‘‰›ǡ˜‘ŽǤͳͷ͹ǡ‘Ǥͺǡ’’Ǥ͵Ͳͳ͸Ȃ͵ͲʹʹǡʹͲͳ͸Ǥ

‘”ƒ†‡• ”‹’–‹‘‘ˆ–Š‡ ‘–”‹„—–‹‘•ƒ†‡–‘–Š‹•ƒ—• ”‹’–„›ǤǤ‡‹‡”’Ž‡ƒ•‡ ”‡ˆ‡”–‘•‡ –‹‘ͳͳǤͳǤ͵‹–Š‡ƒ’’‡†‹šǤ



Inaccordancewithregulations,publicationreprintswereremovedfromthisdissertaǦ tionforthefinalprintversion.





ͷʹ ϳWƌŽũĞĐƚƐ 7.4 InvestigationsoftheCACNA1HS1073Cvariant:EffectsonCYP11B2expresǦ sionandaldosteroneproductionintheadrenocorticalcelllineHAC15in comparisontoCACNA1HM1549V

7.4.1 Objectivesoftheproject ‹ˆˆ‡”‡–—–ƒ–‹‘•‹–Š‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Žͳ Šƒ˜‡„‡‡‹’Ž‹Ǧ ƒ–‡†‹ˆƒ‹Ž‹ƒŽˆ‘”•‘ˆ ͳͳͷǡͳͳͺǡ͵ʹ͹ǡ͵Ͷ͸ǤŠ‡”‡ˆ‘”‡ǡ™Š‡–Š‡CACNA1HS1073C˜ƒ”‹Ǧ ƒ–™ƒ•†‹• ‘˜‡”‡†‹ƒˆƒ‹Ž›™‹–ŠƒŠ‹•–‘”›‘ˆŠ›’‡”–‡•‹‘ǡ‹ Ž—†‹‰–™‘ ’ƒǦ –‹‡–•ǡ–Š‡—–ƒ–‹‘™ƒ• ‘•‹†‡”‡†ƒ’—–ƒ–‹˜‡ ƒ—•‡‘ˆ–Š‡†‹•‡ƒ•‡ǤInvitro•–—†‹‡•‹ ƒƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡™‡”‡ ‘†— –‡†‹‘”†‡”–‘ƒ••‡••–Š‡’‘••‹„‹Ž‹–› ‘ˆ‹ ”‡ƒ•‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘„›—–ƒ– ‡ŽŽ•ǡ™Š‹ Š‹‰Š–Ž‡ƒ†–‘–Š‡†‡˜‡Ž‘’Ǧ ‡–‘ˆ invivoǤ‘–Š‹•‡†ǡ–Š‡‡ˆˆ‡ –•‘ˆ–Š‡—–ƒ–‹‘‘ƒŽ†‘•–‡”‘‡•‡ ”‡–‹‘ ƒ†ƒŽ†‘•–‡”‘‡•›–Šƒ•‡‡š’”‡••‹‘™‡”‡‡ƒ•—”‡†‹ ͳͷ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–Š ™‹Ž†–›’‡ƒ†—–ƒ– Šƒ‡Ž•Ǥ•‹‹Žƒ”ƒ’’”‘ƒ ŠŠƒ•ƒŽ”‡ƒ†›•—’’‘”–‡†–Š‡”‘Ž‡‘ˆ CACNA1HM1549Vƒ•ƒ ƒ—•‡‘ˆ  ͵Ͷ͸Ǥ

7.4.2 MaterialsandMethods

7.4.2.1 Patientsandmutationdiscovery Ž‹‹ ƒŽǡ „‹‘ Š‡‹ ƒŽ ƒ† ‰‡‡–‹  –‡•–‹‰ǡ ‹ Ž—†‹‰ –‡•–‹‰ ˆ‘”  ǡ  ǡ   ȋCACNA1HM1549—–ƒ–‹‘Ȍƒ†‡š‘‡•‡“—‡ ‹‰ǡ™ƒ•’‡”ˆ‘”‡†„›–Š‡‰”‘—’•‘ˆ ”ǤǤƒ”—•‡ǡ”Ǥ Ǥ‡—• ŠŽ‡‹ƒ†”ǤǤǦǤ–”‘™‹–Š–Š‡’ƒ–‹‡–•ǯ‹ˆ‘”‡†™”‹––‡ ‘•‡–ǤŠ‡’ƒ–‹‡–•™‡”‡†‹ƒ‰‘•‡†™‹–Š ƒ–‰‘ƒ ‘•’‹–ƒŽȋ ƒ’ƒȌ‹ƒ ‘”†Ǧ ƒ ‡™‹–Š„‘–Šƒ–‹‘ƒŽƒ†‹•–‹–—–‹‘ƒŽ‰—‹†‡Ž‹‡•ǤŠ‡Ž‘ ƒŽ‡–Š‹ • ‘‹––‡‡ƒ’Ǧ ’”‘˜‡†‘ˆ–Š‡•–—†›Ǥ ƒ•‡”‡’‘”–‘–Š‡‹†‡š ƒ•‡•Šƒ•„‡‡’—„Ž‹•Š‡†„›‘•Š‹†ƒet al.‹ʹͲͳ͹͵Ͷ͹Ǥ

7.4.2.2 Chemicals,buffersandprimers ˆ‘–‹†‹ ƒ–‡††‹ˆˆ‡”‡–Ž›ǡ•–ƒ†ƒ”† Š‡‹ ƒŽ•™‡”‡’—” Šƒ•‡†ƒ–‹‰ƒǦŽ†”‹ Šȋ–Ǥ ‘—‹•ǡǡȌǡ‡” Ǧ‹ŽŽ‹’‘”‡ȋ‹ŽŽ‡”‹ ƒǡǡȌ‘”ƒ”Ž‘–Šȋƒ”Ž•”—Š‡ǡ ‡”Ǧ ƒ›ȌǤ

—ˆˆ‡””‡ ‹’‡•™‹ŽŽ„‡‹†‹ ƒ–‡†‹–Š‡”‡•’‡ –‹˜‡•‡ –‹‘•‘ˆƒ–‡”‹ƒŽ•ƒ†‡–Š‘†•Ǥ –‡”‹Ž‡’Š‘•’Šƒ–‡Ǧ„—ˆˆ‡”‡†•ƒŽ‹‡ȋȌ—•‡†ˆ‘” ‡ŽŽ —Ž–—”‡’—”’‘•‡•™ƒ•’—” Šƒ•‡† ˆ”‘‡” Ǧ‹‘ Š”‘Ǥ

”‹‡”•™‡”‡‘”†‡”‡†ƒ–—”‘ˆ‹• ‹‡–‹ˆ‹ ȋ—š‡„‘—”‰ǡ—š‡„‘—”‰ȌǤ

ͷ͵ ϳWƌŽũĞĐƚƐ 7.4.2.3 Cellculture Š‡ ʹͻͷ•—„ Ž‘‡ ͳͷ™ƒ•ƒ‹†‰‹ˆ–‘ˆ”ǤǤƒ‹‡›͵͵͵ǡ͵͵ͻǤŠ‡ ‡ŽŽ•™‡”‡ —ŽǦ

–—”‡†ƒ–͵͹郐†ͷΨʹ‹ǣ ͳʹȋͳǣͳǡ ‹„ ‘Ȍ ‘–ƒ‹‹‰ͷΨ‘•‹ ƒŽˆ‡”— ȋǡ › Ž‘‡ǡ‘—–Š‘‰ƒǡǡȌǡͳΨ‡‹ ‹ŽŽ‹Ȁ–”‡’–‘› ‹ǡͳؐ‘Ǧ‡••‡–‹ƒŽ ƒ‹‘ƒ ‹†•ǡͳΨ •—Ž‹Ǧ”ƒ•ˆ‡””‹Ǧ‡Ž‡‹—ƒ•™‡ŽŽƒ•ͲǤͳΨŽ‹’‹†‹š–—”‡ȋƒŽŽ ‹„ ‘ȌǤ

‡ŽŽŽ‹‡‹†‡–‹–›™ƒ• ‘ˆ‹”‡†˜‹ƒ•Š‘”––ƒ†‡”‡’‡ƒ–ȋȌ’”‘ˆ‹Ž‹‰—•‹‰–Š‡ ‡ŽŽŽ‹‡ƒ—–Š‡–‹ ƒ–‹‘•‡”˜‹ ‡ȋǡƒƒ••ƒ•ǡǡȌǤ

7.4.2.4 Plasmidsandcloning ‘‰‡‡”ƒ–‡˜‡ –‘”• ƒ””›‹‰–Š‡S1073C—–ƒ–‹‘ǡ–Š‡˜‡ –‘”’͸Ǧ–”›ǦCACNA1H ™‹Ž†–›’‡ȋwtȌ™ƒ•†‹‰‡•–‡†™‹–Š ‘ ȋ‡™‰Žƒ†‹‘Žƒ„•ǡ ’•™‹ ŠǡǡȌƒ† –Š‡Žƒ”‰‡”ˆ”ƒ‰‡–™ƒ•”‡Ž‹‰ƒ–‡†Ǥ”‹‡”•ˆ‘”—‹ Šƒ‰‡™‡”‡†‡•‹‰‡†—•‹‰–Š‡ ”‹‡”  –‘‘Ž ȋˆ™ǣ     Ǣ ”˜ǣ    Ǧ   ȌǤŠ‡•‹–‡Ǧ†‹”‡ –‡†—–ƒ‰‡‡•‹•™ƒ•’‡”ˆ‘”‡†—•‹‰–Š‡ˆ——Ž–”ƒ Š‹‰Šˆ‹†‡Ž‹–›‡œ›‡ȋ‰‹Ž‡–‡ Š‘Ž‘‰‹‡•ǡƒ–ƒŽƒ”ƒǡǡȌˆ‘ŽŽ‘™‹‰–Š‡‹•–”— Ǧ –‹‘•‰‹˜‡„›–Š‡ƒ—ˆƒ –—”‡”Ǥ‡–ƒ‹‡™ƒ•ƒ††‡†–‘–Š‡”‡ƒ –‹‘‹š–‘‹ ”‡ƒ•‡ ”‡ƒ –‹‘‡ˆˆ‹ ‹‡ ›ȋˆ‹ƒŽ ‘ ‡–”ƒ–‹‘ǣͳȌǤ”‹‡ˆŽ›ǡ—‹ Šƒ‰‡™ƒ•’‡”ˆ‘”‡† ‘–Š‡”‡Ž‹‰ƒ–‡†’Žƒ•‹†ȋ ‘†‹–‹‘•ǣͷ‹—–‡•ƒ–ͻͷιǡͳͺ › Ž‡•‘ˆͻͷιͷͲ•ǡͷͷιͷͲ •ǡ͸ͺιͳ͵‹ǡƒ†ƒˆ‹ƒŽ‡Ž‘‰ƒ–‹‘•–‡’‘ˆ͸ͺιˆ‘”ͳ͸‹Ȍˆ‘ŽŽ‘™‡†„›’ †‹‰‡•– ˆ‘”•‡˜‡”ƒŽŠ‘—”•ƒ–͵͹郐†–”ƒ•ˆ‘”ƒ–‹‘‹–‘E.coli–„͵ȋ ˜‹–”‘‰‡„›Š‡”‘ ‹•Š‡” ‹‡–‹ˆ‹ ȌǤŠ‡–”ƒ•ˆ‘”ƒ–•™‡”‡• ”‡‡‡†ˆ‘”–Š‡†‡•‹”‡†—–ƒ–‹‘„›ƒ‰‡” •‡“—‡ ‹‰ȋ‡ ƒ‘—Ž–‡”Ȁ ‡‡™‹œǡ••‡šǡȌ™‹–Š’”‹‡”ͳ ̴•‡“Ͷȋƒ„Ž‡ͷ‹ –Š‡ ƒ’’‡†‹šȌǤ Žƒ•‹†• ƒ””›‹‰ –Š‡ ͳͲ͹͵ —–ƒ–‹‘ ™‡”‡ †‹‰‡•–‡† ™‹–Š –Š‡ ”‡Ǧ •–”‹ –‹‘‡œ›‡•Š‘ ƒ†•’ ȋ‡™‰Žƒ†‹‘Žƒ„•Ȍƒ†Ž‹‰ƒ–‡†‹–‘’͸ǦǦ –”›ǦCACNA1Hwtȋ—•‡†ˆ‘”‡Ž‡ –”‘’Š›•‹‘Ž‘‰›„›”Ǥ ƒ„”‹‡Ž–ÚŽ–‹‰ǡ†ƒ–ƒ‘–•Š‘™Ȍ ƒ†’͸ǦǦCACNA1H Ǧ Ǧ—”‘’”‡˜‹‘—•Ž› —–ƒ––Š‡•ƒ‡”‡•–”‹ –‹‘•‹–‡•Ǥ ‡‡”ƒ–‹‘‘ˆ’͸ǦǦCACNA1Hwt/M1549VǦ Ǧ Ǧ—”‘™ƒ•†‡• ”‹„‡†’”‡˜‹Ǧ ‘—•Ž›͵Ͷ͸Ǥ

Žƒ•‹†•—•‡†ˆ‘”–”ƒ•ˆ‡ –‹‘˜‹ƒ–Š‡ƒšƒ— Ž‡‘ˆ‡ –‘”•›•–‡™‡”‡’”‡’ƒ”‡†™‹–Š –Š‡‹ƒ‰‡†‘ˆ”‡‡ƒš‹‹–ȋ‹ƒ‰‡ǡ ‹Ž†‡ǡ ‡”ƒ›ȌǤ ‘”ƒŽŽ‘–Š‡”’—”’‘•‡•–Š‡ ‹ƒ‰‡ƒš‹Ž—•‹–™ƒ•—•‡†ǤŽƒ•‹†‹†‡–‹–›™ƒ• ‘ˆ‹”‡†‹ƒ ‘–”‘Ž”‡•–”‹ –‹‘ †‹‰‡•–ƒ†ƒ„•‡ ‡‘ˆƒ„‡””ƒ–•‡“—‡ ‡™ƒ• ‘ˆ‹”‡†˜‹ƒƒ‰‡”•‡“—‡ ‹‰—•‹‰ –Š‡’”‹‡”•Ž‹•–‡†‹ƒ„Ž‡ͷ‹–Š‡ƒ’’‡†‹šȋ•‡ –‹‘ͳͳǤ͵ȌǤ

ͷͶ ϳWƌŽũĞĐƚƐ 7.4.2.5 Transfection ‘ƒ••‡••–Š‡‡ˆˆ‡ –•‘ˆCACNA1H—–ƒ–‹‘•invitroǡ–™‘‹ŽŽ‹‘ ͳͷ ‡ŽŽ•ǡ ‘—–‡† ™‹–Šƒ —Ž‹” ‘—–‹‰‘†—Ž‡ȋƒ‘‡ǡ‡‘—Žǡ‘—–Š‘”‡ƒȌǡ™‡”‡–”ƒ•ˆ‡ –‡†™‹–Š ͳρ‰˜‡ –‘”—•‹‰–Š‡’”‘‰”ƒǦͲͷ‘ƒƒšƒ— Ž‡‘ˆ‡ –‘”ʹƒ†–Š‡—Ǧ Ž‡‘ˆ‡ –‘”‹–ȋƒŽŽ‘œƒǡ‘Ž‘‰‡ǡ ‡”ƒ›Ȍˆ‘ŽŽ‘™‹‰–Š‡’”‘–‘ ‘Ž’”‘˜‹†‡†„›–Š‡ ƒ—ˆƒ –—”‡”Ǥˆ–‡”–”ƒ•ˆ‡ –‹‘ǡ ‡ŽŽ•”‡ ‘˜‡”‡†ˆ‘”ͳͷ‹—–‡•ƒ–͵͹鋐 ‡Ǧ †‹—ȋ ‹„ ‘„›Š‡”‘ ‹•Š‡” ‹‡–‹ˆ‹ ǡƒŽ–ŠƒǡǡȌ’”‹‘”–‘•‡‡†‹‰Ǥ‡ –‘”• —•‡†ˆ‘”–”ƒ•ˆ‡ –‹‘™‡”‡CACNA1H  —”‘wt,S1073C,M1549Vƒ•™‡ŽŽƒ• ƒ‡’–›˜‡ –‘” ‘–”‘ŽǤ ‘” ǡ–™‘‹ŽŽ‹‘ ‡ŽŽ•™‡”‡’Žƒ–‡†’‡”™‡ŽŽ‘ˆƒ͸Ǧ™‡ŽŽǦ ’Žƒ–‡Ǥ ‘”“ǡͳǤͷ‹ŽŽ‹‘ ‡ŽŽ•™‡”‡’Žƒ–‡†’‡”™‡ŽŽ‘ˆƒͳʹǦ™‡ŽŽǦ’Žƒ–‡Ǥ— ‡••ˆ—Ž –”ƒ•ˆ‘”ƒ–‹‘™ƒ• ‘ˆ‹”‡†–Š‡‡š–†ƒ›˜‹ƒ ˆŽ—‘”‡• ‡ ‡‹ ”‘• ‘’›Ǥ

‡”— ‘ ‡–”ƒ–‹‘™ƒ•”‡†— ‡†–‘ͲǤͳΨƒ†‡‹ ‹ŽŽ‹Ȁ–”‡’–‘› ‹™ƒ•”‡Ǧ ‘˜‡†ˆ”‘–Š‡‡†‹—ʹͶŠ‘—”•ƒˆ–‡”–”ƒ•ˆ‡ –‹‘Ǥ‘–Š‡”ʹͶŠ‘—”•Žƒ–‡”ǡ–Š‡‡Ǧ †‹—™ƒ• Šƒ‰‡†ƒ‰ƒ‹–‘–Š‡•ƒ‡•‡”—†‡’”‹˜ƒ–‹‘‡†‹—Ǥ͹ʹŠ‘—”•ƒˆ–‡”–”ƒ•Ǧ ˆ‡ –‹‘ǡ‡‹–Š‡”•—’‡”ƒ–ƒ–•™‡”‡Šƒ”˜‡•–‡†ˆ‘” ƒ† ‡ŽŽ•™‡”‡Ž›•‡†ˆ‘”’”‘–‡‹ ƒ••ƒ›‘” ‡ŽŽ•™‡”‡™ƒ•Š‡†™‹–Šƒ†Šƒ”˜‡•–‡†ˆ‘”“Ǥ

7.4.2.6 AldosteroneELISA —’‡”ƒ–ƒ–•™‡”‡•‡––‘–Š‡Žƒ„‘”ƒ–‘”›‘ˆ”Ǥ Ǥ‡—• ŠŽ‡‹ˆ‘”ƒƒŽ›•‹•™‹–Šƒƒ—Ǧ –‘ƒ–‡† Š‡‹Ž—‹‡• ‡–‹—‘ƒ••ƒ›ȋ‹ƒ‹•‘̺‹ƒ‘”‹ǡƒŽ—‰‰‹ƒǡ –ƒŽ›ȌǤŽ†‘•–‡Ǧ ”‘‡ ‘ ‡–”ƒ–‹‘™ƒ•‘”ƒŽ‹œ‡†–‘–‘–ƒŽ•‘Ž—„Ž‡’”‘–‡‹Ǥ ‘”†‡–‡”‹ƒ–‹‘‘ˆ’”‘Ǧ –‡‹ ‘ ‡–”ƒ–‹‘•ǡ ‡ŽŽŽ›•ƒ–‡•™‡”‡†‹Ž—–‡†ͳǣͳͲ‹™ƒ–‡”ƒ†ƒƒŽ›œ‡†—•‹‰–Š‡‹Ǧ ”‘”‘–‡‹••ƒ›‹–ȋŠ‡”‘ ‹‡–‹ˆ‹ „›Š‡”‘ ‹•Š‡” ‹‡–‹ˆ‹ Ȍˆ‘ŽŽ‘™‹‰ –Š‡‹•–”— –‹‘•‰‹˜‡„›–Š‡ƒ—ˆƒ –—”‡”Ǥ

7.4.2.6.1Isolationoftotalsolubleproteinfromcells ‘”‹•‘Žƒ–‹‘‘ˆ–‘–ƒŽ•‘Ž—„Ž‡’”‘–‡‹ǡͶͲͲρ‘ˆ’”‘–‡‹Ž›•‹•„—ˆˆ‡”ȋʹͲ”‹•’ ͹Ǥͷǡ ͳͷͲŽǡͳΨ”‹–‘ǦǦͳͲͲǡͳ–Š›Ž‡‡†‹ƒ‹‡–‡–”ƒƒ ‡–‹ ƒ ‹†ȋȌǡͳ •‘†‹—Ǧ‘”–Š‘˜ƒƒ†ƒ–‡ǡͲǤʹͷŠ‡›Ž‡–Šƒ‡•—Žˆ‘›ŽˆŽ—‘”‹†‡ȋ Ȍƒ†ͳ ‘Ǧ ’Ž‡–‡‹‹‹Š‹„‹–‘” ‘ –ƒ‹Ž–ƒ„Ž‡–ȋ‘ Š‡ǡƒ•‡Žǡ™‹–œ‡”Žƒ†Ȍ’‡”ͷͲȌ™ƒ•ƒ††‡† –‘ ‡ŽŽ•’”‡˜‹‘—•Ž›™ƒ•Š‡†‹Ǥ›•‹•™ƒ•’‡”ˆ‘”‡†ˆ‘”ͳͲ‹—–‡•‘‹ ‡ǤŠ‡ǡ ‡ŽŽ•™‡”‡• ”ƒ’‡†‘ˆˆƒ†–Š‡™Š‘Ž‡Ž›•ƒ–‡™ƒ•–”ƒ•ˆ‡””‡†‹–‘ƒ‹ ”‘ ‡–”‹ˆ—‰‡–—„‡Ǥ ›•ƒ–‡• ™‡”‡ ‡–”‹ˆ—‰‡† ƒ– ˆ—ŽŽ •’‡‡† ƒ† Ͷι ˆ‘” ʹͲ ‹—–‡•Ǥ —’‡”ƒ–ƒ–• ™‡”‡ –”ƒ•ˆ‡””‡†–‘ƒ‡™‹ ”‘ ‡–”‹ˆ—‰‡–—„‡ƒ†•–‘”‡†ƒ–ǦʹͲιǤ

ͷͷ ϳWƌŽũĞĐƚƐ 7.4.2.7 qPCR ‘–ƒŽ™ƒ•‹•‘Žƒ–‡†—•‹‰–Š‡‡ƒ•›‹‹‹–ȋ‹ƒ‰‡Ȍˆ‘ŽŽ‘™‹‰–Š‡‹•–”— –‹‘• ‰‹˜‡„›–Š‡ƒ—ˆƒ –—”‡”ƒ†‹ Ž—†‹‰ƒƒ•‡ †‹‰‡•–‹‘•–‡’Ǥ‡˜‡”•‡–”ƒ• ”‹’–‹‘ ™ƒ•’‡”ˆ‘”‡†—•‹‰͵ͲͲ‰ƒ†–Š‡—ƒ–‹–‡ –‡˜‡”•‡”ƒ• ”‹’–‹‘‹–ȋ‹Ǧ ƒ‰‡Ȍ‹ƒ ‘”†ƒ ‡™‹–Š–Š‡‹•–”— –‹‘•Ǥš’”‡••‹‘Ž‡˜‡Ž•™‡”‡†‡–‡”‹‡†‘ƒ ͹͵ͲͲǦ•›•–‡—•‹‰–Š‡ƒ“ƒ ‡‡š’”‡••‹‘ƒ•–‡”‹šƒ•™‡ŽŽƒ•ƒ ‘Ǧ ‡” ‹ƒŽƒ••ƒ›ˆ‘”GAPDHȋ •Ͳʹ͹ͷͺͻͻͳ̴‰ͳȌƒ†CYP11B2ȋ •Ͳͳͷͻ͹͹͵ʹ̴ͳǡƒ Š‹‡• ƒ†ƒ–‡”‹ƒŽ•„›’’Ž‹‡†‹‘•›•–‡•ǡ ‘•–‡”‹–›ǡǡȌǤƒ’Ž‡•™‡”‡‡ƒ•—”‡†‹

–”‹’Ž‹ ƒ–‡•ƒ†”‡•—Ž–•™‡”‡ƒƒŽ›œ‡†—•‹‰–Š‡ʹǦȟȟȋǣŠ”‡•Š‘Ž†› Ž‡Ȍ‡–Š‘†͵ͶͺǤ

 ™ƒ•—•‡†ƒ•–Š‡”‡ˆ‡”‡ ‡‰‡‡ƒ†ʹǦȟȟ˜ƒŽ—‡•™‡”‡ ƒŽ —Žƒ–‡†”‡Žƒ–‹˜‡–‘ ‡’–›˜‡ –‘”Ǧ–”ƒ•ˆ‡ –‡† ‡ŽŽ•Ǥ

7.4.2.8 Statisticalanalysisandsoftware ƒ–ƒ™ƒ•ƒƒŽ›œ‡†—•‹‰–Š‡”‹••‘ˆ–™ƒ”‡ȋ ”ƒ’Šƒ†ǡƒ ‘ŽŽƒǡǡȌƒ†š ‡Ž ȋ‹ ”‘•‘ˆ–ǡ‡†‘†ǡǡȌǤŽŽ‡””‘”„ƒ”•”‡’”‡•‡–•–ƒ†ƒ”†‡””‘”‘ˆ–Š‡‡ƒ ȋȌǤƒ–ƒƒƒŽ›•‹•™ƒ•’‡”ˆ‘”‡†™‹–Šƒ—’ƒ‹”‡†ǡ–™‘Ǧ–ƒ‹Ž‡†–—†‡–ǯ•–Ǧ–‡•–Ǥ

”ƒ™‹‰•™‡”‡ƒ†‡—•‹‰ • ƒ’‡ȋ ”‡‡‘ˆ–™ƒ”‡ ‘—†ƒ–‹‘ǡ‘•–‘ǡǡȌƒ† ‘™‡”‘‹–ȋ‹ ”‘•‘ˆ–ȌǤInsilicoƒƒŽ›•‹•‘ˆ–Š‡CACNA1HS1073Cƒ†ARMC5A656S —–ƒ–‹‘–‘’”‡†‹ ––Š‡‹”’‘–‡–‹ƒŽˆ‘”†ƒƒ‰‡‘ˆ’”‘–‡‹ˆ— –‹‘™ƒ•’‡”ˆ‘”‡†„› ‘—” ’ƒ”–‡” ‰”‘—’• —•‹‰ –Š‡ ‘Ž›‘”’Š‹• Š‡‘–›’‹‰ ˜ʹ –‘‘Ž ȋƒ˜ƒ‹Žƒ„Ž‡ ˆ”‘ Š––’ǣȀȀ‰‡‡–‹ •Ǥ„™ŠǤŠƒ”˜ƒ”†Ǥ‡†—Ȁ’’ŠʹȀȌǤ‡“—‡ ‹‰”‡•—Ž–•™‡”‡ƒƒŽ›œ‡†™‹–Š‡Ǧ “—‡ Š‡”ͶǤ͹ȋ†‡‘˜‡”•‹‘ǡ ‡‡‘†‡•‘”’‘”ƒ–‹‘”„‘”ǡ ǡȌǤ ˆ‘–•–ƒ–‡† †‹ˆˆ‡”‡–Ž›ǡƒŽŽ‡Ž‡ˆ”‡“—‡ ‹‡•™‡”‡‘„–ƒ‹‡†ˆ”‘–Š‡š‘‡‰‰”‡‰ƒ–‹‘‘•‘”–‹— ȋšȌ†ƒ–ƒ„ƒ•‡ǡƒ˜ƒ‹Žƒ„Ž‡ˆ”‘Š––’ǣȀȀ‡šƒ Ǥ„”‘ƒ†‹•–‹–—–‡Ǥ‘”‰Ȁ͵ͶͻǤ ˆ‘–•–ƒ–‡†‘–Š‡”Ǧ ™‹•‡ǡ•‹‰Ž‡— Ž‡‘–‹†‡’‘Ž›‘”’Š‹•ȋȌ •™‡”‡‘„–ƒ‹‡†ˆ”‘–Š‡ƒ–ƒ„ƒ•‡‘ˆ ‹‰Ž‡— Ž‡‘–‹†‡‘Ž›‘”’Š‹••ȋ†„ȌǤ‡–Š‡•†ƒȋȌǣƒ–‹‘ƒŽ‡–‡”ˆ‘”‹‘Ǧ –‡ Š‘Ž‘‰› ˆ‘”ƒ–‹‘ǡ ƒ–‹‘ƒŽ ‹„”ƒ”› ‘ˆ ‡†‹ ‹‡Ǥ ˜ƒ‹Žƒ„Ž‡ˆ”‘ǣ Š––’ǣȀȀ™™™Ǥ „‹ǤŽǤ‹ŠǤ‰‘˜ȀȀǤ ‡‘‹  ’‘•‹–‹‘• ‘ˆ —–ƒ–‹‘• ™‡”‡ ‘„–ƒ‹‡† ˆ”‘–Š‡‰‡‘‡„”‘™•‡”ƒ ‡••‹‰Š—ƒ‰‡‘‡„—‹Ž†ͳͻȋƒ˜ƒ‹Žƒ„Ž‡ ˆ”‘ Š––’ǣȀȀ‰‡‘‡Ǥ— • Ǥ‡†—ȀȌǤ

7.4.3 Results  ‘”†‡” –‘ ‹†‡–‹ˆ› ’—–ƒ–‹˜‡ †‹•‡ƒ•‡Ǧ ƒ—•‹‰ ˜ƒ”‹ƒ–•ǡ ‡š‘‡ •‡“—‡ ‹‰ ™ƒ• ’‡”Ǧ ˆ‘”‡†‘‘‘œ›‰‘–‹ –™‹•†‹ƒ‰‘•‡†™‹–Š ƒ†–Š”‡‡‘ˆ–Š‡‹” Š‹Ž†”‡ƒˆ–‡”‡šǦ Ž—•‹‘‘ˆ–Š”‡‡‡•–ƒ„Ž‹•Š‡†ˆ‘”•‘ˆ ǡƒ‡Ž›  ǡ  ƒ†  ȋ—–ƒ–‹‘‹

ͷ͸ ϳWƌŽũĞĐƚƐ CACNA1HM1549ȌǤŠ‹•–‘”›‘ˆŠ›’‡”–‡•‹‘™ƒ•‡•–ƒ„Ž‹•Š‡†‹–Š‡ˆƒ‹Ž›ȋ ‹‰—”‡͹ȌǤ Ž‹‹ ƒŽƒ†„‹‘ Š‡‹ ƒŽ’ƒ”ƒ‡–‡”•‘ˆ–Š‡‹†‡š’ƒ–‹‡–•Šƒ˜‡ƒŽ”‡ƒ†› „‡‡ ’—„Ǧ Ž‹•Š‡†͵Ͷ͹ǤŠ‡ Š‹Ž†”‡‘ˆ–Š‡‹†‡š ƒ•‡•ƒ”‡ƒŽŽ‘”‘–‡•‹˜‡ǡ™‹–Š–Š‡‡š ‡’–‹‘‘ˆ ‘‡•‘ȋ Ǧ͵ǡ ‹‰—”‡͹Ȍ’”‡•‡–‹‰™‹–Š™Š‹–‡ ‘ƒ–Š›’‡”–‡•‹‘Ǥ‘–ƒ„Ž›ǡƒŽŽ–Š‡ ‹†‡š ƒ•‡•™‡”‡ˆ‹”•–†‹ƒ‰‘•‡†™‹–ŠŠ›’‡”–‡•‹‘™Š‡ƒ’’”‘š‹ƒ–‡Ž›ͶͲ›‡ƒ”•‘Ž† ƒ†ƒŽŽ‘ˆ–Š‡‹” Š‹Ž†”‡™‡”‡‹–Š‡‹”–Š‹”–‹‡•™Š‡–Š‹••–—†›™ƒ• ‘†— –‡†͵Ͷ͹Ǥ

š‘‡•‡“—‡ ‹‰”‡˜‡ƒŽ‡†ƒCACNA1HS1073C—–ƒ–‹‘ȋ Š”‘‘•‘‡ͳ͸ǣͳʹͷͺͲ͹͸ ε ǡ„ƒ•‡†‘Š—ƒ‰‡‘‡„—‹Ž†ͳͻȌ‹ˆ‘—”ˆƒ‹Ž›‡„‡”•ǣ‹Ǥ‡Ǥ–Š‡–™‘‹†‡š ƒ•‡• ƒ†–™‘‘ˆ–Š‡‹” Š‹Ž†”‡ȋ ‹‰—”‡͹ǡǡȌǤŠ‡—–ƒ–‹‘‹•Ž‘ ƒ–‡†‹–Š‡Ž‹‡””‡‰‹‘ „‡–™‡‡–ƒ•‡„”ƒ‡•‡‰‡–•͸‘ˆŠ‘‘Ž‘‰‘—•”‡’‡ƒ– ƒ†ͳ‘ˆ”‡’‡ƒ– ‘ˆ –Š‡ͳ ’”‘–‡‹ȋ ‹‰—”‡͹ȌǤŠ‡CACNA1HS1073C˜ƒ”‹ƒ–ȋ”•͵͸ͻͶ͹ͶͷͲͲȌ‹• Ž‹•–‡†‹–Š‡š†ƒ–ƒ„ƒ•‡ǡ™Š‡”‡‹–™ƒ•”‡’‘”–‡†‹ͳ‡„‡”‘ˆƒƒ•–•‹ƒ’‘’—Ǧ Žƒ–‹‘ȋƒŽŽ‡Ž‡ˆ”‡“—‡ ›ǣͳǤ͸ͶͷȉͳͲǦͷȌǤ‘ Ž‹‹ ƒŽ”‡Ž‡˜ƒ ‡Šƒ•„‡‡”‡’‘”–‡†‘–Š‹• ǤInsilicoƒƒŽ›•‹• Žƒ••‹ˆ‹‡†–Š‡—–ƒ–‹‘ƒ•’‘••‹„Ž›†ƒƒ‰‹‰–‘’”‘–‡‹ˆ— –‹‘Ǥ

‘‹˜‡•–‹‰ƒ–‡ƒ•—•’‡ –‡†”‘Ž‡‹ ǡ™‡’‡”ˆ‘”‡†ƒinvitroƒƒŽ›•‹•–‘‹˜‡•–‹‰ƒ–‡ –Š‡‡ˆˆ‡ –•‘ˆ–Š‡—–ƒ–‹‘‘CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡ Š—ƒƒ†”‡‘ ‘”–‹ ƒŽ ‡ŽŽŽ‹‡ ͳͷȋ ‹‰—”‡ͺȌǤCYP11B2‡š’”‡••‹‘™ƒ••Ž‹‰Š–Ž›‹Ǧ ”‡ƒ•‡†ȋ̱ͳǤͺǦˆ‘Ž†Ȍ‹ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–ŠCACNA1Hwt‹ ‘’ƒ”‹•‘™‹–Š‡’–› ˜‡ –‘”Ǧ–”ƒ•ˆ‡ –‡† ‡ŽŽ•ǡ ™Š‹ Š ‹• ‹ Ž‹‡ ™‹–Š ‘—” ’”‡˜‹‘—• ”‡’‘”–͵Ͷ͸Ǥ ‘ †‹ˆˆ‡”‡ ‡ ‘—Ž†„‡†‡–‡ –‡†‹ ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–ŠCACNA1Hwt‹ ‘’ƒ”‹•‘–‘CACNA1H S1073CǤ‡ŽŽ•–”ƒ•ˆ‡ –‡†™‹–ŠCACNA1HM1549Vƒ•ƒ’‘•‹–‹˜‡ ‘–”‘Ž•Š‘™ƒ•‹‰‹ˆ‹Ǧ ƒ– ‹ ”‡ƒ•‡ ‹ CYP11B2 ‡š’”‡••‹‘ ȋ̱͵Ǥ͹Ǧˆ‘Ž†ǡ ’αͲǤͲͲͲͺȌ ‹ ‘’ƒ”‹•‘ ™‹–Š wtǦ –”ƒ•ˆ‡ –‡† ‡ŽŽ•ǡ ™Š‹ Š ‹• ‹ ƒ‰”‡‡‡– ™‹–Š ‘—” ’”‡˜‹‘—• •–—†› ‘ ͳ  ͳͷͶͻ͵Ͷ͸ȋ ‹‰—”‡ͺȌǤ–—†‹‡•‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹–Š‡•‡ ‡ŽŽ•’”‘˜‹†‡•‹Ǧ ‹Žƒ” ”‡•—Ž–•ǡ •Š‘™‹‰ ƒ ‹ ”‡ƒ•‡‹ CACNA1H wtǦ–”ƒ•ˆ‡ –‡† ‡ŽŽ• ‹ ‘’ƒ”‹•‘ –‘ –Š‘•‡–”ƒ•ˆ‡ –‡†™‹–Š‡’–›˜‡ –‘”ȋ̱ʹǤͶǦˆ‘Ž†ȌǤ‘†‹ˆˆ‡”‡ ‡™ƒ•†‡–‡ –‡†„‡–™‡‡ CACNA1Hwtƒ†S1073Cǡ™Š‹Ž‡–”ƒ•ˆ‡ –‹‘™‹–ŠCACNA1HM1549V”‡•—Ž–‡†‹ƒ•‹‰Ǧ ‹ˆ‹ ƒ– ‹ ”‡ƒ•‡ ‹ ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ‹ ‘’ƒ”‹•‘ –‘ –Š‡ wtȋ̱ͶǤ͸Ǧˆ‘Ž†ǡ ’δͲǤͲͲͲͳǡ ‹‰—”‡ͺȌǤ

—”–Š‡”‘”‡ǡ‘†‹ˆˆ‡”‡ ‡„‡–™‡‡ͳ ™–ƒ†ͳͲ͹͵™ƒ•ˆ‘—†‹‡Ž‡ –”‘Ǧ ’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡•‹˜‡•–‹‰ƒ–‹‰ Šƒ‡Žƒ –‹˜ƒ–‹‘ƒ††‡ƒ –‹˜ƒ–‹‘Ȁ‹ƒ –‹˜ƒ–‹‘‹ ʹͻ͵ ‡ŽŽ•ȋ’‡”ˆ‘”‡†„›”Ǥ ƒ„”‹‡Ž–ÚŽ–‹‰ǡ†ƒ–ƒ‘–•Š‘™ȌǤ

ͷ͹ ϳWƌŽũĞĐƚƐ



&ŝŐƵƌĞϳ͘Eϭ,^ϭϬϳϯ͘ͿWĞĚŝŐƌĞĞŽĨƚŚĞŬŝŶĚƌĞĚŝŶǀĞƐƚŝŐĂƚĞĚŝŶƚŚŝƐǁŽƌŬ͘ZŽƵŶĚƐLJŵďŽůƐƌĞƉƌĞƐĞŶƚ ĨĞŵĂůĞƐ͕ƐƋƵĂƌĞƐLJŵďŽůƐƌĞƉƌĞƐĞŶƚŵĂůĞƐ͘sĞƌƚŝĐĂůůŝŶĞƐŝŶĚŝĐĂƚĞĚĞƐĐĞŶƚ͘dŝůƚĞĚůŝŶĞƐǁŝƚŚĂǀĞƌƚŝĐĂůĐŽŶŶĞĐƚŽƌ ƐƚĂŶĚĨŽƌŵŽŶŽnjLJŐŽƚŝĐƚǁŝŶƐ͘///ͲϭĂŶĚ///ͲϮĂƌĞƚŚĞŝŶĚĞdžĐĂƐĞƐ͘/ŶĚŝǀŝĚƵĂůƐŵĂƌŬĞĚŝŶďůĂĐŬŚĂǀĞďĞĞŶĚŝĂŐͲ ŶŽƐĞĚǁŝƚŚW,͕ŽƚŚĞƌŚLJƉĞƌƚĞŶƐŝǀĞŝŶĚŝǀŝĚƵĂůƐĂƌĞŵĂƌŬĞĚŝŶŐƌĞLJ͘'ĞŶĞƚŝĐĂŶĂůLJƐŝƐ͕ŝŶĐůƵĚŝŶŐĞdžŽŵĞƐĞͲ ƋƵĞŶĐŝŶŐ͕ŚĂƐďĞĞŶƉĞƌĨŽƌŵĞĚŽŶŝŶĚŝǀŝĚƵĂůƐŵĂƌŬĞĚǁŝƚŚĂƐƚĞƌŝƐŬƐ͘ͿEƐĞƋƵĞŶĐŝŶŐƌĞƐƵůƚƐŽĨĂůůϱĨĂŵŝůLJ ŵĞŵďĞƌƐŽďƚĂŝŶĞĚďLJ^ĂŶŐĞƌ^ĞƋƵĞŶĐŝŶŐ͘&ŽƵƌĨĂŵŝůLJŵĞŵďĞƌƐĐĂƌƌLJƚŚĞEϭ,^ϭϬϳϯŵƵƚĂƚŝŽŶ͕ǁŚŝůĞ ŽŶĞĚŝƐƉůĂLJƐƚŚĞǁŝůĚƚLJƉĞƐĞƋƵĞŶĐĞĂƚƚŚŝƐƉŽƐŝƚŝŽŶ;^ĞƋƵĞŶĐŝŶŐǁĂƐƉĞƌĨŽƌŵĞĚďLJŽƵƌĐŽŽƉĞƌĂƚŝŽŶƉĂƌƚŶĞƌƐ ĂŶĚƚŚŝƐĚĞƉŝĐƚŝŽŶǁĂƐŝŶĐůƵĚĞĚŚĞƌĞǁŝƚŚƉĞƌŵŝƐƐŝŽŶŽĨƌ͘&͘ĞƵƐĐŚůĞŝŶͿ͘ͿDƵƚĂƚŝŽŶƐŝŶEϭ,͕,ϭ ĂŶĚZDϱĨŽƵŶĚŝŶƚŚĞŝŶǀĞƐƚŝŐĂƚĞĚĨĂŵŝůLJŵĞŵďĞƌƐďLJĞdžŽŵĞƐĞƋƵĞŶĐŝŶŐ͘ͿEϭ,^ϭϬϳϯŝƐůŽĐĂƚĞĚ ŝŶƚŚĞůŝŶŬĞƌƌĞŐŝŽŶďĞƚǁĞĞŶƚƌĂŶƐŵĞŵďƌĂŶĞƐĞŐŵĞŶƚƐ^ϲŽĨŚŽŵŽůŽŐŽƵƐƌĞƉĞĂƚ//ĂŶĚ^ϭŽĨƌĞƉĞĂƚ///͘ 

š‘‡•‡“—‡ ‹‰”‡˜‡ƒŽ‡†–Š‡ˆ—”–Š‡”—–ƒ–‹‘•ǡ‹Ǥ‡ǤARMC5 A656S,ȋ Š”‘‘•‘‡ ͳ͸ǣ͵ͳͶ͹͹ʹ͹ʹ ε͕ ˆ‘—† ‹ ƒŽŽ ˆ‹˜‡ ˆƒ‹Ž› ‡„‡”•ǡ ‹‰—”‡ ͹ Ȍ ƒ† DACH1 ͳͷͶ̴ͳͷͷ†—’ ȋ Š”‘‘•‘‡ ͳ͵ǣ͹ʹͶͶͲͶͶ͵ ε   „ƒ•‡† ‘ Š—ƒ ‰‡‘‡ „—‹Ž†ͳͻǡˆ‘—†‹Ͷˆƒ‹Ž›‡„‡”•ǡ ‹‰—”‡͹Ȍǡ‰‡‡•’”‡˜‹‘—•Ž›‹’Ž‹ ƒ–‡†‹  ‘””‡‰—Žƒ–‹‘‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘ͺ͸ǡ͵ʹͻǤInsilicoƒƒŽ›•‹• Žƒ••‹ˆ‹‡†–Š‡ARMC5—Ǧ –ƒ–‹‘ ƒ• ’”‘„ƒ„Ž› †ƒƒ‰‹‰ –‘ ’”‘–‡‹ ˆ— –‹‘Ǥ Š‡ —–ƒ–‹‘ ‹• ”‡ˆ‡”‡ ‡† ƒ• ”•͹ͷ͵Ͳͺͺ͸͵ͻ‹†„ǤŠ‡šƒ–ƒ„ƒ•‡”‡’‘”–•ƒˆ”‡“—‡ ›‘ˆͺǤ͵Ͳ͸ȉͳͲǦ͸ˆ‘”–Š‹• ˜ƒ”‹ƒ–Ǥ –•Š‘—Ž†„‡‘–‡†–Šƒ––Š‡šƒ–ƒ„ƒ•‡”‡ˆ‡”‡ ‡•‘Ž›–Š‡‰‡‘‹ ’‘•‹Ǧ –‹‘‘ˆ–Š‡„—–‘–‹–• ǤŠ‡DACH1S154_S155dup˜ƒ”‹ƒ–ȋ”•ͷͷͳͻ͵ͷͳͶͲȌ ƒ„‡ˆ‘—†‹–Š‡šƒ–ƒ„ƒ•‡ǡ™Š‡”‡‹–Šƒ•ƒ”‡’‘”–‡†ƒŽŽ‡Ž‡ˆ”‡“—‡ ›‘ˆ ͲǤͳʹ͸ͳȉͳͲǦ͵Ǥˆ‘–‡ǡ–Š‹•—–ƒ–‹‘‹•”‡ˆ‡”‡ ‡†ƒ•”•͹͹͵Ͳʹ͵Ͳ͹Ͷ‹†„ǡ™‹–Š–Š‡

ͷͺ ϳWƌŽũĞĐƚƐ ‰‡‘‡„”‘™•‡”•–ƒ–‹‰ƒƒŽŽ‡Ž‡ˆ”‡“—‡ ›‘ˆͲǤͻ͸ʹ͹͵Ǥ‡™‡”‡—ƒ„Ž‡–‘‹†‡Ǧ –‹ˆ›–Š‡‘”‹‰‹•‘ˆ–Š‹•†‹• ”‡’ƒ ›ǤŽ‹‹ ƒŽ”‡Ž‡˜ƒ ‡Šƒ•‘–„‡‡”‡’‘”–‡†ˆ‘”–Š‹•

˜ƒ”‹ƒ–Ǥ





&ŝŐƵƌĞϴ͘zWϭϭϮĞdžƉƌĞƐƐŝŽŶͿĂŶĚĂůĚŽƐƚĞƌŽŶĞƉƌŽĚƵĐƚŝŽŶͿŝŶ,ϭϱĐĞůůƐƚƌĂŶƐĨĞĐƚĞĚǁŝƚŚĞŵƉƚLJǀĞĐͲ ƚŽƌ͕Eϭ,ǁƚ͕^ϭϬϳϯŽƌDϭϱϰϵs͘ƌƌŽƌďĂƌƐƌĞƉƌĞƐĞŶƚƐƚĂŶĚĂƌĚĞƌƌŽƌŽĨƚŚĞŵĞĂŶ͘^ŝŐŶŝĨŝĐĂŶĐĞƐŽĨƌĞͲ ƐƵůƚƐĂƌĞŝŶĚŝĐĂƚĞĚďLJŶƐ;ŶŽƚƐŝŐŶŝĨŝĐĂŶƚͿĨŽƌƉхϬ͘Ϭϱ͕ΎΎΎWчϬ͘ϬϬϭ͘EƵŵďĞƌŽĨďŝŽůŽŐŝĐĂůƌĞƉůŝĐĂƚĞƐĂŶĂůLJnjĞĚ ĂƌĞĨŽƌͿŶсϰĨŽƌĞŵƉƚLJǀĞĐƚŽƌ͕ǁƚ͕^ϭϬϳϯĂŶĚŶсϮĨŽƌDϭϱϰϵs͕ĨŽƌͿŶсϭϬĨŽƌĞŵƉƚLJǀĞĐƚŽƌ͕ǁƚ͕^ϭϬϳϯ ĂŶĚŶсϲĨŽƌDϭϱϰϵs͘ 

7.4.4 Conclusions –Š‹••–—†›ǡ–Š‡˜ƒ”‹ƒ–CACNA1HS1073C™ƒ•‹†‡–‹ˆ‹‡†‹‡„‡”•‘ˆƒˆƒ‹Ž›™‹–Š ƒŠ‹•–‘”›‘ˆŠ›’‡”–‡•‹‘ǡ‹ Ž—†‹‰–™‘ˆƒ‹Ž›‡„‡”•†‹ƒ‰‘•‡†™‹–Š Ǥ‹ ‡ —–ƒ–‹‘•‹CACNA1HŠƒ˜‡’”‡˜‹‘—•Ž›„‡‡‹’Ž‹ ƒ–‡†‹ ƒ†insilicoƒƒŽ›•‹• Žƒ••‹ˆ‹‡†ͳ ͳͲ͹͵ƒ•’‘••‹„Ž›†ƒƒ‰‹‰ǡ–Š‡—–ƒ–‹‘™ƒ• ‘•‹†‡”‡†ƒ’—Ǧ –ƒ–‹˜‡ ƒ—•‡‘ˆ–Š‡†‹•‡ƒ•‡ͳͳͷǡͳͳͺǡ͵Ͷ͸Ǥ ‘™‡˜‡”ǡ–”ƒ•ˆ‡ –‹‘™‹–ŠCACNA1HS1073C†‹† ‘– Šƒ‰‡ ‡‹–Š‡” ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ‘” CYP11B2 ‡š’”‡••‹‘ ‹ ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽ•‹ ‘’ƒ”‹•‘–‘CACNA1Hwtǡ™Š‹Ž‡–Š‡’”‡˜‹‘—•Ž›‹’Ž‹ ƒ–‡†˜ƒ”‹ƒ– CACNA1HM1549V Ž‡ƒ”Ž›†‹†ǤŠ‡”‡ˆ‘”‡ǡ‹–‹•Ž‹‡Ž›–Šƒ–CACNA1HS1073C‹•‘––Š‡ ƒ—•‡‘ˆ ‹–Š‡•‡’ƒ–‹‡–•ǤŠ‹• ‘ Ž—•‹‘‹••—’’‘”–‡†„›–Š‡Žƒ ‘ˆ‡ˆˆ‡ –‘ˆ–Š‡ ͳͲ͹͵ —–ƒ–‹‘ ‘ ͳ  Šƒ‡Ž ƒ –‹˜ƒ–‹‘ ƒ† ‹ƒ –‹˜ƒ–‹‘ǡ ’”‘’‡”–‹‡• –Šƒ– Šƒ˜‡„‡‡•Š‘™–‘„‡ƒŽ–‡”‡†‹ͳ ͳͷͶͻ—–ƒ– Šƒ‡Ž•‹’”‡˜‹‘—••–—†Ǧ ‹‡•ͳͳͷǡͳͳͺǤ™‘‘–Š‡”—–ƒ–‹‘•‹‰‡‡•’”‡˜‹‘—•Ž›‹’Ž‹ ƒ–‡†–‘’Žƒ›ƒ”‘Ž‡‹ƒŽ†‘•–‡Ǧ ”‘‡’”‘†— –‹‘‘” ǡƒ‡Ž›DACH1S154_S155dupƒ†ARMC5A656SǡŠƒ˜‡‘– „‡‡–Š‡•—„Œ‡ –‘ˆinvitroƒƒŽ›•‡•‹–Š‹••–—†›ƒ†‹‰Š–„‡–Š‡ ƒ—•‡‘ˆ ‹–Š‡

ͷͻ ϳWƌŽũĞĐƚƐ ’ƒ–‹‡–• †‡• ”‹„‡† ƒ„‘˜‡Ǥ ‘™‡˜‡”ǡ ƒ ’‘••‹„Ž› Š‹‰Š ƒŽŽ‡Ž‡ ˆ”‡“—‡ › ‘ˆ –Š‡ DACH1 S154_S155dup˜ƒ”‹ƒ– ŠƒŽŽ‡‰‡•‹–•’‘•‹–‹‘ƒ•ƒŽ‹‡Ž› ƒ†‹†ƒ–‡Ǥ

 

͸Ͳ ϴŝƐĐƵƐƐŝŽŶ 8 Discussion Š‡•–—†‹‡•‹ Ž—†‡†‹–Š‹•™‘”ƒŽŽ•Šƒ”‡–Š‡ ‘‘‰‘ƒŽ‘ˆ„”‘ƒ†‡‹‰‘—”—†‡”Ǧ •–ƒ†‹‰‘ˆ–Š‡—†‡”Ž›‹‰‡ Šƒ‹••‘ˆ Ǥ –Š‹•’”‘ ‡••ǡ–Š‡‹˜‡•–‹‰ƒ–‹‘‘ˆ  ƒ—•‡•ƒ†–Š‡‹”†‹•–‹ –‹˜‡ Šƒ”ƒ –‡”‹•–‹ •ƒ•™‡ŽŽƒ•–Š‡‡š’Ž‘”ƒ–‹‘‘ˆ‘’–‹‘•ˆ‘”†‹Ǧ ƒ‰‘•‹•ƒ†–”‡ƒ–‡–ƒ”‡‘ˆ’ƒ”–‹ —Žƒ”‹–‡”‡•–ǤŠ‡ˆ‘ŽŽ‘™‹‰•‡ –‹‘•™‹ŽŽ†‹• —•• Š‘™‘—”ƒ‹ˆ‹†‹‰•ˆ‹–‹™‹–Š‘–Š‡””‡’‘”–•ǡŠ‘™–Š‡› ‘–”‹„—–‡–‘‘—”—†‡”•–ƒ†Ǧ ‹‰‘ˆ ƒ†‹™Šƒ–™ƒ›•–Š‡›‹‰Š–‹ˆŽ—‡ ‡†‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘’–‹‘•ˆ‘”  ’ƒ–‹‡–•Ǥ

8.1 APAmutationsandtheircorrelationwithpatientandtumorcharacteristics ”‡ ‡–›‡ƒ”•ǡ”‡ —””‡–•‘ƒ–‹ —–ƒ–‹‘•‹ƒ˜ƒ”‹‡–›‘ˆ‰‡‡•Šƒ˜‡„‡‡†‡• ”‹„‡† ‹•ȋ ‘’ƒ”‡•‡ –‹‘͸Ǥ͵ǤʹǤͳ‘ˆ–Š‡‹–”‘†— –‹‘ȌǤ‹ ”‡ƒ•‹‰ƒ‘—–‘ˆ•–—†‹‡• ‘ˆ˜ƒ”›‹‰•‹œ‡Šƒ•„‡‡’‡”ˆ‘”‡†‘†‹ˆˆ‡”‡–’‘’—Žƒ–‹‘•ȋˆ‘”ƒ‘˜‡”˜‹‡™•‡‡ƒ„Ž‡ ͳ‹–Š‡‹–”‘†— –‹‘ȌǤ ‘™‡˜‡”ǡˆ‹†‹‰•Šƒ˜‡‘–ƒŽ™ƒ›•„‡‡‹ƒ‰”‡‡‡–™‹–Š‡ƒ Š ‘–Š‡”ǡ™Š‹ Š‹‰Š–ˆ‘”‡šƒ’Ž‡„‡†—‡–‘†‹ˆˆ‡”‹‰†‹ƒ‰‘•‹• ”‹–‡”‹ƒǡ‹Š‡”‡–’‘’—ŽƒǦ –‹‘†‹ˆˆ‡”‡ ‡•‘”‹•—ˆˆ‹ ‹‡–•–ƒ–‹•–‹ ƒŽ’‘™‡”ȋ ‘’ƒ”‡‡Ǥ‰Ǥͳͷ͹ǡʹ͵͹ǡʹͶ͹ȌǤ

Š‹Ž‡KCNJ5—–ƒ–‹‘•‹•Šƒ˜‡„‡‡‡š–‡•‹˜‡Ž› ‘˜‡”‡†‹–Š‡Ž‹–‡”ƒ–—”‡ǡ™‹–Šƒ ‡–ƒǦƒƒŽ›•‹•‘ˆ‘˜‡”ͳ͸ͲͲ’ƒ–‹‡–•ƒ˜ƒ‹Žƒ„Ž‡ǡ‘–Š‡”—–ƒ–‹‘•–Šƒ–‘ —”‘”‡”ƒ”‡Ž› Šƒ˜‡„‡‡•–—†‹‡†–‘ƒŽ‡••‡”‡š–‡†ȋ ‘’ƒ”‡ʹͶ͹ƒ†ƒ„Ž‡ͳ‹–Š‡‹–”‘†— –‹‘ȌǤŠ‡ ʹͲͳͷ•–—†›„› Š‘ŽŽetal.ˆ‡ƒ–—”‡†‹–Š‹•™‘” ‘˜‡”•—–ƒ–‹‘•‹–Š‡ˆ‹˜‡ƒ‹‰‡‡• —””‡–Ž›‹’Ž‹ ƒ–‡†‹•ǣKCNJ5ǡATP1A1ǡATP2B3,CACNA1Dƒ†CTNNB1ȋ ‘Ǧ ’ƒ”‡•‡ –‹‘͸Ǥ͵ǤʹǤͳ‘ˆ–Š‡‹–”‘†— –‹‘ȌǤ

8.1.1 Mutationfrequenciesarelargelyinaccordancewithpreviousreports —–ƒ–‹‘ˆ”‡“—‡ ‹‡•ˆ‘—†‹‘—”•–—†›ƒ”‡‘•–Ž›‹Ž‹‡™‹–Š‘–Š‡””‡’‘”–•ǣKCNJ5 —–ƒ–‹‘•™‡”‡ˆ‘—†‹͵͹ǤͳΨ‘ˆ•ǡ™Š‹ Š‹•‹ƒ ‘”†ƒ ‡™‹–Š‘–Š‡”ˆ‹†‹‰•‹ ‡•–‡” ‘Š‘”–•ȋ ‘’ƒ”‡ƒ„Ž‡ͳȌǤŽ•‘ ‘ —””‹‰™‹–Š‘–Š‡””‡’‘”–•ǡG151R™ƒ•–Š‡ ‘•–ˆ”‡“—‡–Ž›ˆ‘—†—–ƒ–‹‘‹KCNJ5ȋʹ͵Ǥ͹ΨȌǡˆ‘ŽŽ‘™‡†„›–Š‡L168R—–ƒ–‹‘ ȋͻǤ͵ΨȌǤ——•—ƒŽŽ›Š‹‰Š—„‡”‘ˆƒ††‹–‹‘ƒŽ‘˜‡ŽKCNJ5—–ƒ–‹‘•™ƒ•ˆ‘—†ǡ‹Ǥ‡Ǥ F154CǡI150_G151insMǡI157KǡS143_I144insIAȋ•‡‡͵ͷͲȀ•‡ –‹‘͹ǤͳǤʹƒ†ˆ‘” ‘’ƒ”‹•‘ ™‹–Š‘–Š‡”•–—†‹‡•ƒ„Ž‡͸‹–Š‡ƒ’’‡†‹šȌǤ

—–ƒ–‹‘•‹CACNA1D™‡”‡†‹• ‘˜‡”‡†‹ͳͲǤ͵Ψ‘ˆ•ǡ™Š‹ Š‹•‘–Š‡Š‹‰Š‡”‡† ‘ˆ™Šƒ–‘–Š‡”•–—†‹‡•”‡’‘”–ȋ ‘’ƒ”‡ƒ„Ž‡ͳ‹–Š‡‹–”‘†— –‹‘ȌǤ –•Š‘—Ž†„‡‘–‡† –Šƒ–‹–Š‹••–—†›ǡ–™‘CACNA1D—–ƒ–‹‘•„‡ ƒ‡‘Ž›ƒ’’ƒ”‡–‹‡š‘‡•‡“—‡ ‹‰Ǥ ‹ ‡–Š‡‰‡‡”ƒŽ’”‘ ‡†—”‡ˆ‘”–Š‡†‡–‡ –‹‘‘ˆCACNA1D—–ƒ–‹‘•‹‘—” ‘Š‘”–™ƒ•

͸ͳ ϴŝƐĐƵƐƐŝŽŶ ƒ‰‡”•‡“—‡ ‹‰‘ˆ—–ƒ–‹‘Š‘–•’‘–•ǡ‹–‹•’‘••‹„Ž‡–Šƒ––Š‡†‡–‡ –‡†—–ƒ–‹‘ˆ”‡Ǧ “—‡ ›‹•ƒ—†‡”‡•–‹ƒ–‡͵ͷͲǤŠ‡•ƒ‡‹•–”—‡ˆ‘”‘–Š‡”•–—†‹‡•–Šƒ–‘•–Ž›‘”‡š Ž—Ǧ •‹˜‡Ž›”‡Ž›‘ƒ•‹‹Žƒ”•–”ƒ–‡‰›ǡ™Š‹ Šƒ’’Ž‹‡•–‘ƒŽŽ•–—†‹‡•Ž‹•–‡†‹ƒ„Ž‡͹‹–Š‡ ƒ’’‡†‹šǤŠ‹•‹‰Š–„‡ƒ‹†‹ ƒ–‘”–Šƒ–CACNA1D—–ƒ–‹‘•ƒ –—ƒŽŽ›‘ —”‘”‡ˆ”‡Ǧ “—‡–Ž›‹•–Šƒ–Š‡ —””‡–Ž‹–‡”ƒ–—”‡•—‰‰‡•–•Ǥ‹‹Žƒ”–‘’”‡˜‹‘—•”‡’‘”–•ǡG403R ™ƒ•–Š‡‘•–ˆ”‡“—‡–Ž›ˆ‘—†—–ƒ–‹‘‹CACNA1Dȋ͸ǤʹΨȌǤŽŽ‘–Š‡”—–ƒ–‹‘•™‡ ‹†‡–‹ˆ‹‡†‹CACNA1DŠƒ˜‡’”‡˜‹‘—•Ž›„‡‡”‡’‘”–‡†ͳʹͳǡʹ͸ʹȋƒŽ•‘ ‘’ƒ”‡ƒ„Ž‡͹‹ –Š‡ƒ’’‡†‹šȌǤ

Š‡ˆ”‡“—‡ ›‘ˆATP1A1—–ƒ–‹‘•ȋͺǤʹΨȌ‹‘—””‡’‘”–‹•‘–Š‡Š‹‰Š‡”‡†‘ˆˆ”‡Ǧ “—‡ ‹‡• ”‡’‘”–‡† „› ‘–Š‡” •–—†‹‡•ǡ ™Š‹Ž‡ –Š‡ ‘ —””‡ ‡ ‘ˆ ƒŽ–‡”ƒ–‹‘• ‹ ATP2B3 ȋ͵ǤͳΨȌˆ‹–•‹–Š‡‹††Ž‡‘ˆ–Š‡’”‡˜‹‘—•Ž›‘„•‡”˜‡†”ƒ‰‡ȋ ‘’ƒ”‡ƒ„Ž‡ͳ‹–Š‡‹Ǧ –”‘†— –‹‘ȌǤ‹‹Žƒ”–‘’”‡˜‹‘—•”‡’‘”–•L104R‹•–Š‡‘•– ‘‘Ž›ˆ‘—†—–ƒ–‹‘ ‹ATP1A1ȋ͹ǤʹΨȌǤ—–ƒ–‹‘•‹ATP2B3ˆ‘—†‹•ƒ”‡‘•–Ž›†‡Ž‡–‹‘•ƒˆˆ‡ –‹‰ –Š‡ͳʹ͵Ǧͳʹͻ”‡‰‹‘ȋ ‘’ƒ”‡ʹͶͶǡʹͶͻǡʹͷͷǡʹ͸ʹƒ†ƒ„Ž‡ͺ‹–Š‡ƒ’’‡†‹šȌǤŠ‡”‡ˆ‘”‡ǡ –Š‡‘˜‡ŽͶʹ͸ ̴Ͷʹ͹̴Ͷʹͺ̴Ͷ͵͵†‡Ž˜ƒ”‹ƒ–‹‘ǡ ‘•‹•–‹‰‘ˆƒ ‘„‹‡†‹••‡•‡ —–ƒ–‹‘ƒ††‡Ž‡–‹‘ǡ‹••‘‡™Šƒ–†‹•–‹ –‹˜‡ȋ ‘’ƒ”‡͵ͷͲȀ•‡ –‹‘͹ǤͳǤʹȌǤ

‘–ƒ›”‡’‘”–•‘—–ƒ–‹‘ˆ”‡“—‡ ‹‡•‹CTNNB1‹Žƒ”‰‡” ‘Š‘”–•ƒ”‡ƒ˜ƒ‹ŽǦ ƒ„Ž‡ǤŠ‡ʹǤͳ؏—–ƒ–‹‘ˆ”‡“—‡ ›ˆ‘—†‹‘—”•–—†›‹••Ž‹‰Š–Ž›„‡Ž‘™–Š‘•‡”‡’‘”–‡† „›‘–Š‡”•ǡ„—––ƒ‹‰‹–‘ƒ ‘—–Ž‹‹–‡†•ƒ’Ž‡•‹œ‡ƒ†–Š‡”‡Žƒ–‹˜‡Ž›”ƒ”‡‘ —”Ǧ ”‡ ‡‘ˆCTNNB1—–ƒ–‹‘•ǡ–Š‹•‹••–‹ŽŽ™‹–Š‹–Š‡ƒ”‰‹‘ˆ‡””‘”ȋ ‘’ƒ”‡ʹ͹ͳǡʹ͹͸ƒ† ƒ„Ž‡ͳ‹–Š‡‹–”‘†— –‹‘ȌǤ ƒ ‘”†ƒ ‡™‹–Š’”‡˜‹‘—•”‡’‘”–•ǡƒŽŽ—–ƒ–‹‘•ƒ”‡Ž‘Ǧ ƒ–‡†‹‡š‘͵ʹͶͷǡʹ͹ͳǡʹ͹͸ǤŠ‡‘•–ˆ”‡“—‡–Ž›”‡’‘”–‡†ͶͷƒŽ–‡”ƒ–‹‘™ƒ•ƒŽ•‘†‡Ǧ –‡ –‡†‹‘—” ‘Š‘”–ȋ ‘’ƒ”‡‡Ǥ‰Ǥʹ͹ͳǡʹ͹͸ƒ†ƒ„Ž‡ͻ‹–Š‡ƒ’’‡†‹šȌǤ

8.1.2 Mutationsrelatetopatientandtumorcharacteristics •–ƒ„Ž‹•Š‹‰ ‘””‡Žƒ–‹‘•„‡–™‡‡‘™—–ƒ–‹‘•ƒ†–Š‡ Ž‹‹ ƒŽƒ†”ƒ†‹‘Ž‘‰Ǧ ‹ ƒŽ’Š‡‘–›’‡‘ˆ–Š‡’ƒ–‹‡–•‹‰Š–ˆƒ ‹Ž‹–ƒ–‡†‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–‘ˆ–Š‡’ƒ–‹‡–•Ǥ ‡ ”‹–‹ ƒŽˆƒ –‘”‹†‹ƒ‰‘•‹•‹•ƒ†”‡ƒŽ˜‡‹•ƒ’Ž‹‰ȋȌǡ’‡”ˆ‘”‡†–‘‡•Ǧ –ƒ„Ž‹•Š—‹Žƒ–‡”ƒŽŽ›‹ ”‡ƒ•‡†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ǤŠ‹•‹˜ƒ•‹˜‡–‡ Š‹“—‡‹• ‘Ǧ ’Ž‹ ƒ–‡†–‘’‡”ˆ‘”ƒ†–Š‡”‡ˆ‘”‡”‡“—‹”‡•ƒ‡š’‡”‹‡ ‡†”ƒ†‹‘Ž‘‰‹•–ʹ͵ͳǤŠ‡”‡ˆ‘”‡ǡ‹– ™‘—Ž†„‡†‡•‹”ƒ„Ž‡–‘ƒ˜‘‹†‹–‹ ƒ•‡•™Š‡”‡”‡Ž‹ƒ„Ž‡†‹ƒ‰‘•‹•‘ˆ ƒ„‡ƒ Š‹‡˜‡† „›‘–Š‡”‡ƒ•Ǥ

͸ʹ ϴŝƐĐƵƐƐŝŽŶ ‹–Š”‡‰ƒ”†–‘’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •ǡ™‡ˆ‘—†ƒ•‹‰‹ˆ‹ ƒ–ˆ‡ƒŽ‡’”‡Ǧ †‘‹ƒ ‡ƒ‘‰’ƒ–‹‡–•™‹–ŠKCNJ5Ǧ—–ƒ–‡†–—‘”•Ǥ—‘”• ƒ””›‹‰KCNJ5—Ǧ –ƒ–‹‘•™‡”‡ƒŽ•‘Žƒ”‰‡”–Šƒ„‘–Š™‹Ž†–›’‡–—‘”•ƒ†–—‘”• ƒ””›‹‰—–ƒ–‹‘•‹ ‘–Š‡”‰‡‡•͵ͷͲǤŠ‹•‹•‹Ž‹‡™‹–Šƒ˜ƒ”‹‡–›‘ˆ’”‡˜‹‘—•”‡’‘”–•ƒ†™ƒ• ‘ˆ‹”‡†„› ‡–ƒǦƒƒŽ›•‹•ȋ ‘’ƒ”‡‡Ǥ‰Ǥ ͳͷ͹ǡʹ͵͹ǡʹͶ͹ǡ͵ͷͳƒ†ƒ„Ž‡͸‹–Š‡ƒ’’‡†‹šȌǤ —”–Š‡”‘”‡ǡ KCNJ5—–ƒ––—‘”•™‡”‡ˆ‘—†–‘„‡‘”‡Ž‹‡Ž›‘ˆ ǦŽ‹‡ƒ’’‡ƒ”ƒ ‡ǡ ‘•‹•–‹‰ ‘ˆ‘•–Ž›Žƒ”‰‡ Ž‡ƒ” ‡ŽŽ•™‹–ŠŽ‹’‹††”‘’Ž‡–•ȋ ‘’ƒ”‡ ͵ͷͲȀ•‡ –‹‘͹ǤͳǤʹȌǤŠ‹• ‘‹Ǧ ‹†‡†™‹–ŠŽ‘™‡”’”‡Ǧ ‘–”ƒ•– ‘—•ˆ‹‡Ž†‹–•‹ƒƒŽ›•‹•ǡ™Š‹ Š‹•‹†‹ ƒ–‹˜‡‘ˆ Ž‘™‡”–—‘”†‡•‹–›ȋ ‘’ƒ”‡͵ͷͲȀ•‡ –‹‘͹ǤͳǤʹȌǤ ǦŽ‹‡ƒ’’‡ƒ”ƒ ‡‹KCNJ5—–ƒ– –—‘”•Šƒ•’”‡˜‹‘—•Ž›„‡‡†‡• ”‹„‡†‹•‘‡•–—†‹‡•ʹͷ͸ȂʹͷͺǤ

ƒ•‡†‘–Š‡•‡ˆ‹†‹‰•–‘‰‡–Š‡”™‹–Š–Š‡ˆ”‡“—‡–‘„•‡”˜ƒ–‹‘‘ˆ›‘—‰‡”ƒ‰‡‹’ƒǦ –‹‡–•™‹–ŠKCNJ5—–ƒ–•ǡ™Š‹ Š™ƒ• ‘ˆ‹”‡†„›‡–ƒǦƒƒŽ›•‹•ǡ‘—”•–—†›•—‰Ǧ ‰‡•–•–Šƒ– ‘—Ž†„‡‘‹––‡†‹–Š‡†‹ƒ‰‘•‹•‘ˆ›‘—‰ˆ‡ƒŽ‡’ƒ–‹‡–•™‹–ŠŽƒ”‰‡ ƒ†‡‘ƒ’”‡•‡–‹‰™‹–ŠŽ‘™ ‘—•ˆ‹‡Ž†—‹–•‹ƒ• ƒ͵ͷͲǤ ‘” ƒ•‡•™‹–Šƒ•‡˜‡”‡ ’Š‡‘–›’‡ǡ–Š‹•™‘—Ž†„‡‹Ž‹‡™‹–Š —””‡–‰—‹†‡Ž‹‡•‘ˆ–Š‡‡†‘ ”‹‡•‘ ‹Ǧ ‡–›ʹ͵ͳǤˆ‘–‡ǡƒ•‡˜‡”‡ ’Š‡‘–›’‡‹•ƒˆ‡ƒ–—”‡–Šƒ–Šƒ•ƒŽ•‘„‡‡†‡• ”‹„‡†–‘„‡ ‘”‡ ‘‘‹’ƒ–‹‡–•™‹–ŠKCNJ5—–ƒ––—‘”•–Šƒ‹–Š‘•‡™‹–Š‘—–‹–Š‡’ƒ•– ȋ ‘’ƒ”‡‡Ǥ‰ǤʹͶ͹ǡ͵ͷͳƒ†ƒ„Ž‡͸‹–Š‡ƒ’’‡†‹šȌǤ

ƒ††‹–‹‘ǡ‹‘—”•–—†›ǡ’ƒ–‹‡–•™‹–Š‘ǦKCNJ5—–ƒ–‹‘•™‡”‡‘”‡ˆ”‡“—‡–Ž› ƒŽ‡ǡ™Š‹ Š‹•‹ƒ ‘”†ƒ ‡™‹–Š’”‡˜‹‘—•”‡’‘”–•ƒƒŽ›œ‹‰ƒ•‡ƒ†CACNA1D —–ƒ–‹‘•ʹͶͻǡʹ͸ͻǤ‘ ‘””‡Žƒ–‹‘™‹–Šƒ Ǧ‘”ƒ ǦŽ‹‡’Š‡‘–›’‡™ƒ•ˆ‘—†ˆ‘”‘Ǧ KCNJ5Ǧ—–ƒ–‡†–—‘”•‹ ‘’ƒ”‹•‘–‘™‹Ž†–›’‡–—‘”•Ǥ‡’‘”–•‘–Š‡Š‹•–‘Ž‘‰‹ ƒŽ ƒ’’‡ƒ”ƒ ‡‘ˆƒ•‡ƒ†CACNA1D—–ƒ––—‘”•˜ƒ”›ǡ‡‹–Š‡””‡’‘”–‹‰ ǦŽ‹‡ƒ’Ǧ ’‡ƒ”ƒ ‡ˆ‘”‘‡‘”„‘–Š–›’‡•‘ˆ‰‡‡—–ƒ–‹‘•‘”‘ ‘””‡Žƒ–‹‘ȋ ‘’ƒ”‡ʹͷͷǡʹ͸ʹǡʹ͸ͻ ƒ†ƒ„Ž‡͹ǡƒ„Ž‡ͺ‹–Š‡ƒ’’‡†‹šȌǤ

8.1.3 Conclusionandoutlook Š‹••–—†›Šƒ•„”‘ƒ†‡‡†–Š‡‹ˆ‘”ƒ–‹‘‘ ‘””‡Žƒ–‹‘„‡–™‡‡—–ƒ–‹‘ƒŽ•–ƒǦ –—•™‹–Š–—‘”ƒ†’ƒ–‹‡– Šƒ”ƒ –‡”‹•–‹ •ǡˆ—”–Š‡” ‘ˆ‹”‹‰ƒ˜ƒ”‹‡–›‘ˆ‘„•‡”˜ƒ–‹‘• ƒ†‡„›’”‡˜‹‘—••–—†‹‡•Ǥ ‘™‡˜‡”ǡŽ‹‡Ž›†—‡–‘–Š‡‹”Š‹‰Š’”‡˜ƒŽ‡ ‡ǡKCNJ5—–ƒ– •”‡ƒ‹–Š‡„‡•–Ǧ Šƒ”ƒ –‡”‹œ‡†‘‡•Ǥ‘”‡†‡–ƒ‹Ž‡†‹ˆ‘”ƒ–‹‘‘–Š‡†‹•–‹ –‹˜‡ ˆ‡ƒ–—”‡•‘ˆ–—‘”• ƒ””›‹‰ƒ•‡ƒ†CACNA1D—–ƒ–‹‘•‹ ‘’ƒ”‹•‘–‘‡ƒ Š ‘–Š‡”ƒ†–‘™‹Ž†–›’‡–—‘”•™‘—Ž†„‡†‡•‹”ƒ„Ž‡–‘‹’”‘˜‡‘—”‘™Ž‡†‰‡‘ˆ•

͸͵ ϴŝƐĐƵƐƐŝŽŶ ™‹–Š–Š‡„‡‡ˆ‹–‘ˆ’ƒ–‹‡–•™‹–Š–Š‡•‡”ƒ”‡”—–ƒ–‹‘•‹‹†Ǥ•’‡ ‹ƒŽŽ›CTNNB1—Ǧ –ƒ–‹‘•‹•ƒ”‡‘–™‡ŽŽǦ Šƒ”ƒ –‡”‹œ‡†•‘ˆƒ”ǡ„—–‘”‡‡š–‡•‹˜‡•–—†‹‡•Šƒ˜‡„‡‡ ‘†— –‡†”‡ ‡–Ž›ʹ͹ͳǡʹ͹͸Ǥ

8.2 MacrolidesareblockersofKCNJ5mutantchannels –Š‡ʹͲͳ͹•–—†›„› Š‘ŽŽetal.‹ Ž—†‡†‹–Š‹•™‘”ǡƒŠ‹‰ŠǦ–Š”‘—‰Š’—–• ”‡‡‘ˆ ‘˜‡” ͹͵ǡͲͲͲ ‘’‘—†• ™ƒ• ’‡”ˆ‘”‡† –‘ ‹†‡–‹ˆ› ‹Š‹„‹–‘”• ‘ˆ  ͷ ͳͷͳ ƒ† ͳ͸ͺ Šƒ‡Ž•™Š‹ Š†‘‘–‹Š‹„‹––Š‡™‹Ž†–›’‡Ǥ—Ž–‹’Ž‡ ‘’‘—†•„‡Ž‘‰‹‰–‘ –Š‡ˆƒ‹Ž›‘ˆƒ ”‘Ž‹†‡•™‡”‡ˆ‘—†–‘‡‡––Š‡•‡ ”‹–‡”‹ƒǡ”‘š‹–Š”‘› ‹„‡‹‰–Š‡ ‘•–‡ˆˆ‡ –‹˜‡‘‡͵ͷʹǤ

ƒ ”‘Ž‹†‡•ƒ”‡ƒˆƒ‹Ž›‘ˆƒ–‹„‹‘–‹  ‘’‘—†•ǤŠ‡‹”ƒ‹•–”— –—”ƒŽ‡Ž‡‡–‹•ƒͳʹǦ ͳ͸ƒ–‘Žƒ –‘‡”‹‰͵ͷ͵ǤŠ‡‹”ƒ–‹„‹‘–‹ ƒ –‹˜‹–›‹•„ƒ•‡†‘‹Š‹„‹–‹‘‘ˆ„ƒ –‡”‹ƒŽ’”‘Ǧ –‡‹•›–Š‡•‹•–Š”‘—‰Š„‹†‹‰‘ˆʹ͵•”‹–Š‡ͷͲ•”‹„‘•‘‡͵ͷ͵ǡ͵ͷͶǤ ƒ ”‘Ž‹†‡• ‘•–Ž›ƒˆˆ‡ –‰”ƒǦ’‘•‹–‹˜‡„ƒ –‡”‹ƒǡ„—–ƒ”‡ƒŽ•‘‡ˆˆ‡ –‹˜‡–”‡ƒ–‡–•ˆ‘”‹ˆ‡ –‹‘• ™‹–ŠLegionella,Chlamydiaƒ†MycoplasmaǤŠ‡›ƒ”‡ƒˆ”‡“—‡– Š‘‹ ‡‹–Š‡–”‡ƒ–Ǧ ‡–‘ˆ”‡•’‹”ƒ–‘”›–”ƒ –‹ˆ‡ –‹‘•ƒ•™‡ŽŽƒ••‘ˆ––‹••—‡ƒ†•‹‹ˆ‡ –‹‘•͵ͷ͵ǡ͵ͷͶǤ‡Ǧ •‹•–ƒ ‡–‘ƒ ”‘Ž‹†‡• ƒ„‡ƒ “—‹”‡†„›•—• ‡’–‹„Ž‡„ƒ –‡”‹ƒƒ†Šƒ•„‡‡‘„•‡”˜‡† ‹—Ž–‹’Ž‡•–”ƒ‹•͵ͷ͵ǡ͵ͷͶǤ

ƒ–—”ƒŽƒ ”‘Ž‹†‡•–‡†–‘„‡‹•–ƒ„Ž‡‹‰ƒ•–”‹ ƒ ‹†ƒ†–‘Šƒ˜‡—†‡•‹”ƒ„Ž‡’Šƒ”ƒǦ ‘‹‡–‹ •Ǥ‘‹’”‘˜‡†”—‰’‡”ˆ‘”ƒ ‡ǡ Š‡‹ ƒŽ’”‘ ‡••‹‰•— Šƒ••ƒŽ–ˆ‘”ƒ–‹‘ ‘”–Š‡‹–”‘†— –‹‘‘ˆ•–”— –—”ƒŽ‘†‹ˆ‹ ƒ–‹‘•Šƒ˜‡„‡‡’‡”ˆ‘”‡†ǡ”‡•—Ž–‹‰‹–Š‡ †‡˜‡Ž‘’‡– ‘ˆ •‡‹•›–Š‡–‹  ƒ ”‘Ž‹†‡• •— Š ƒ• Žƒ”‹–Š”‘› ‹ ƒ† ”‘š‹–Š”‘›Ǧ ‹͵ͷ͵Ǥ  ‘–”ƒ•––‘‘–Š‡”ƒ ”‘Ž‹†‡•ǡ”‘š‹–Š”‘› ‹Šƒ•ƒ”‡Žƒ–‹˜‡Ž›Š‹‰Š„‹‘ƒ˜ƒ‹Žƒ„‹ŽǦ ‹–›ȋ͹ʹǦͺͲΨ˜‡”•—•͵ͲǦͷͷΨȌǤƒ ”‘Ž‹†‡•ƒ”‡ƒ„Ž‡–‘‹Š‹„‹––Š‡‡œ›‡͵Ͷǡ™Š‹ Š ‹•ƒ‡„‡”‘ˆ–Š‡ ›–‘ Š”‘‡ͶͷͲˆƒ‹Ž›ƒ†‹•‹˜‘Ž˜‡†‹–Š‡‡–ƒ„‘Ž‹œƒ–‹‘‘ˆƒ ˜ƒ”‹‡–›‘ˆ†”—‰•ǤŠ‹• ƒŽ‡ƒ†–‘’”‘„Ž‡ƒ–‹ †”—‰‹–‡”ƒ –‹‘•͵ͷͷǤŠ‡‘•– ‘‘ ƒ†˜‡”•‡‡ˆˆ‡ –•‘ˆƒ ”‘Ž‹†‡•ƒ”‡‰ƒ•–”‘‹–‡•–‹ƒŽ”‡ƒ –‹‘•ǡ ƒ—•‡†„›‘–‹Ž‹‹†— Ǧ –‹‘͵ͷ͸ǤŠ‹•‘–‹Ž‹†‡ˆ— –‹‘Šƒ•„‡‡•— ‡••ˆ—ŽŽ›•‡’ƒ”ƒ–‡†ˆ”‘ƒ–‹„‹‘–‹ ˆ— –‹‘ „› Š‡‹ ƒŽ‘†‹ˆ‹ ƒ–‹‘͵ͷ͹Ǥ‡•‹†‡•ƒ–‹„ƒ –‡”‹ƒŽƒ†‘–‹Ž‹†‡ˆ— –‹‘ǡƒ–‹Ǧ‹ˆŽƒǦ ƒ–‘”›‡ˆˆ‡ –•‘ˆƒ ”‘Ž‹†‡•Šƒ˜‡„‡‡†‡• ”‹„‡†͵ͷͺǤ

Š‡‡ Šƒ‹••–Š”‘—‰Š™Š‹ Šƒ ”‘Ž‹†‡•‹Š‹„‹– ͷ Šƒ‡Ž•ƒ”‡—‘™•‘ ˆƒ”ǡƒŽ–Š‘—‰Šƒ‹–‡”ƒ –‹‘™‹–Š–Š‡ Šƒ‡Ž’‘”‡™‘—Ž†„‡ ‘ ‡‹˜ƒ„Ž‡Ǥˆ‘–‡ǡ‹–ƒ’Ǧ ’‡ƒ”•–Šƒ––Š‡Žƒ –‘‡”‹‰ƒ† Žƒ†‹‘•‡•—‰ƒ”‘ˆ”‘š‹–Š”‘› ‹ƒ”‡ ”‹–‹ ƒŽ‡Ž‡‡–•

͸Ͷ ϴŝƐĐƵƐƐŝŽŶ ‹ ͷ„Ž‘ ƒ‰‡͵ͷʹǤ  Šƒ‡Ž•–”— –—”‡•Šƒ˜‡„‡‡‹˜‡•–‹‰ƒ–‡†„›’”‘–‡‹ ”›•Ǧ –ƒŽŽ‘‰”ƒ’Š›‹–Š‡’ƒ•–ǡ™Š‹ Š‹‰Š–ƒŽ•‘’”‘˜‡ƒˆ‡ƒ•‹„Ž‡‘’–‹‘Š‡”‡ȋ ‘’ƒ”‡‡Ǥ‰Ǥ ͳ͸Ͳǡͳͺ͸ȌǤ

8.2.1 KCNJ5channelblockersreducealdosteroneproductionandgivenewimǦ pulsesforthediagnosisandtreatmentofPHApatients ‘—”•–—†›ǡ”‘š‹–Š”‘› ‹ƒ•™‡ŽŽƒ•–Š‡‘Ǧƒ–‹„‹‘–‹  ‘’‘—†͵ͺ”‡†— ‡† CYP11B2‡š’”‡••‹‘‹ ʹͻͷ ‡ŽŽ•‡š’”‡••‹‰KCNJ5G151Rƒ†L158R™‹–Š‘—–ƒˆˆ‡ –Ǧ ‹‰–Š‡™‹Ž†–›’‡ȋ͵ͷʹȀ•‡ –‹‘͹ǤʹǤʹȌǤ‘š‹–Š”‘› ‹ƒŽ•‘”‡†— ‡†ƒŽ†‘•–‡”‘‡’”‘†— Ǧ –‹‘‹•–ƒ„Ž›–”ƒ•ˆ‡ –‡† ͳͷ ‡ŽŽ•ǡƒ‰ƒ‹‘–’”‘†— ‹‰ Šƒ‰‡•‹–Š‡™‹Ž†–›’‡͵ͷʹ ȋ•‡ –‹‘͹ǤʹǤʹȌǤŠ‹•‹†‹ ƒ–‡•–Šƒ–”‡†— ‡† Šƒ‡Žƒ –‹˜‹–›‹•†‹”‡ –Ž›Ž‹‡†–‘”‡†— ‡† ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ǡ •—‰‰‡•–‹‰ –Šƒ– ƒ •‹‹Žƒ” ‡ˆˆ‡ – ‘—Ž† „‡ ƒ Š‹‡˜‡† in vivoǤ Žƒ•ƒ ‘ ‡–”ƒ–‹‘•‘ˆ”‘š‹–Š”‘› ‹™‹–Š‹–Š‡ ‘ ‡–”ƒ–‹‘”ƒ‰‡–Šƒ–‹†— ‡† •‹‰‹ˆ‹ ƒ–‡ˆˆ‡ –•in vitroŠƒ˜‡„‡‡”‡’‘”–‡†‹’ƒ–‹‡–•ȋ—’–‘ͳͻǤͷρ‡ƒ•—”‡† •Š‘”–Ž›ƒˆ–‡”•‹‰Ž‡†‘•‡ƒ†‹‹•–”ƒ–‹‘ǡ ‘’ƒ”‡†–‘•‹‰‹ˆ‹ ƒ–invitro‡ˆˆ‡ –•„‡‹‰ ‘„•‡”˜‡†„‡–™‡‡ͷƒ†ʹͲρ”‘š‹–Š”‘› ‹͵ͷʹǡ͵ͷͻǡ•‡ –‹‘͹ǤʹǤʹȌǤ

™‘’‘••‹„Ž‡—•‡•ˆ‘”ƒ ”‘Ž‹†‡•‹–Š‡ ‘—”•‡‘ˆ†‹ƒ‰‘•‹•ƒ†–”‡ƒ–‡–ƒ”‡‹Ǧ ƒ‰‹ƒ„Ž‡ǣ ‹”•–ǡ–Š‡› ‘—Ž†„‡—•‡†‹–Š‡†‹ƒ‰‘•‹•‘ˆ ’ƒ–‹‡–•™‹–Š•—•’‡ –‡†Ǥ –Š‡‘”›ǡƒ†”‘’‹ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•‹”‡•’‘•‡–‘ƒ•Š‘”––‡”ƒ†‹‹•–”ƒ–‹‘‘ˆ ”‘š‹–Š”‘› ‹™‘—Ž†„‡‹†‹ ƒ–‹˜‡‘ˆKCNJ5—–ƒ–Ǥ‘•‡“—‡–Ž›ǡ‹–‹‰Š–„‡ ’‘••‹„Ž‡–‘ˆ‘”‰‘‹–Š‡•‡’ƒ–‹‡–•͵ͷʹǤ‡ ‘†ǡƒ ”‘Ž‹†‡• ‘—Ž†•‡”˜‡ƒ•ƒ‘Ǧ •—”‰‹ ƒŽ–”‡ƒ–‡–‘’–‹‘‹’ƒ–‹‡–•™‹–ŠKCNJ5—–ƒ–•Ǥ ‘™‡˜‡”ǡ–‘ƒ˜‘‹†”‡Ǧ •‹•–ƒ ‡•ǡ‘Ǧƒ–‹„‹‘–‹ ƒ ”‘Ž‹†‡••Š‘—Ž†„‡—•‡†–‘–Š‹•‡†ǤŠ‡invitro‡š’‡”‹Ǧ ‡–•—•‹‰͵ͺ•Š‘™–Šƒ–ƒ‡ˆˆ‡ –‹˜‡„Ž‘ ƒ‰‡‘ˆ ͷ—–ƒ– Šƒ‡Ž• ƒ„‡ •‡’ƒ”ƒ–‡†ˆ”‘ƒ–‹„‹‘–‹ ’”‘’‡”–‹‡•‹ƒ ”‘Ž‹†‡•͵ͷʹȋ•‡ –‹‘͹ǤʹǤʹȌǤ –Šƒ•„‡‡•—‰Ǧ ‰‡•–‡†–Šƒ–ˆ‘”ƒ–‹‘‹KCNJ5—–ƒ––—‘”•‹•†—‡–‘’”‘Ž‹ˆ‡”ƒ–‹‘‹”‡•’‘•‡ –‘‹ ”‡ƒ•‡†‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪ ƒ—•‡†„›‹ˆŽ—š–Š”‘—‰Š˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž• —’‘‡„”ƒ‡†‡’‘Žƒ”‹œƒ–‹‘ȋ ‘’ƒ”‡ͳͻ͹ƒ† ‹‰—”‡ͷ‹–Š‡‹–”‘†— –‹‘ȌǤ‡’‘”–• ‘ˆƒ••‹˜‡ƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒ‹’ƒ–‹‡–• ƒ””›‹‰‰‡”Ž‹‡KCNJ5G151R—–ƒ–‹‘• ‘”ƒ’ƒ–‹‡–†‹•’Žƒ›‹‰Š›’‡”’Žƒ•–‹ Ž‡•‹‘•†—‡–‘‰‡‡–‹ ‘•ƒ‹ ‹•ˆ—”–Š‡”•—’’‘”– –Šƒ–‘–‹‘ȋ ‘’ƒ”‡‡Ǥ‰Ǥ͵ͳͳǡ͵ͳͻǡ͵ͷʹǡƒ„Ž‡͵ƒ†•‡ –‹‘͸Ǥ͵ǤʹǤʹǤ͵‹–Š‡‹–”‘†— –‹‘ȌǤ Š‡”‡ˆ‘”‡ǡ’”‡˜‡–‹‘‘ˆ†‡’‘Žƒ”‹œƒ–‹‘–Š”‘—‰Š„Ž‘ ƒ‰‡‘ˆ—–ƒ– ͷ Šƒ‡Ž• ‹‰Š–•–‘’–Š‹•‡ˆˆ‡ –Ǥ•‹œ‡‹‰Š–‡˜‡„‡‡”‡†— ‡†‘”–Š‡–—‘”‹‰Š–†‹•ƒ’’‡ƒ” ‘’Ž‡–‡Ž›͵ͷʹǤ— Šƒ‡ˆˆ‡ –Šƒ•„‡‡‘„•‡”˜‡†‹’‹–—‹–ƒ”›’”‘Žƒ –‹‘ƒǡ™Š‡”‡”‡Ǧ

͸ͷ ϴŝƐĐƵƐƐŝŽŶ †— ‡†’”‘Žƒ –‹‘—–’—–ƒ•™‡ŽŽƒ•–—‘”•Š”‹ƒ‰‡ƒ”‡‘ˆ–‡ƒ Š‹‡˜‡†„›†‘’ƒ‹‡ƒ‰Ǧ ‘‹•–•Ǥ •‘‡’ƒ–‹‡–•ǡ–—‘”•”‡ ‡†‡ ‘’Ž‡–‡Ž›ǡ™Š‹ ŠƒŽŽ‘™•ˆ‘”†‹• ‘–‹—ƒ–‹‘ ‘ˆ–”‡ƒ–‡–͵͸ͲǤ

Š‡„‡‡ˆ‹–•‘ˆƒ ”‘Ž‹†‡–”‡ƒ–‡–ˆ‘”  ’ƒ–‹‡–•ƒ”‡†‹ˆˆ‹ —Ž––‘’”‡†‹ –ǤŠ‹Ž‡ ’ƒ–‹‡–•™‹–ŠG151R—–ƒ–‹‘•‹‰Š–Ž‹‡Ž›’”‘ˆ‹–ˆ”‘ƒ ”‘Ž‹†‡–”‡ƒ–‡–ǡ‡ˆˆ‡ –•‘ ‘–Š‡”—–ƒ–‹‘•”‡ƒ‹–‘„‡‹˜‡•–‹‰ƒ–‡†Ǥˆ‘–‡ǡ’”‡Ž‹‹ƒ”›‡š’‡”‹‡–•‹‘—”Žƒ„ Šƒ˜‡•—‰‰‡•–‡†–Šƒ–CYP11B2‡š’”‡••‹‘‹ͳͷͺ—–ƒ– ‡ŽŽ•‹‰Š–‘–„‡ƒˆˆ‡ –‡† „›”‘š‹–Š”‘› ‹ȋ†ƒ–ƒ‘–•Š‘™ȌǤ‘–Š‡”‹’‘”–ƒ–ˆƒ –‘”–‘ ‘•‹†‡”‹•–Šƒ–ǡ„‡Ǧ ƒ—•‡  ’ƒ–‹‡–• ƒ””›‰‡”Ž‹‡—–ƒ–‹‘•ǡ ͷ—–ƒ– Šƒ‡Ž•™‹ŽŽ‘–‘Ž› „‡‡š’”‡••‡†‹–Š‡ƒ†”‡ƒŽ‰Žƒ†ǡ„—–ƒŽ•‘‹‘–Š‡”–‹••—‡•Ž‹‡–Š‡Š‡ƒ”–‹–Š‡•‡’ƒǦ –‹‡–•ȋ ‘’ƒ”‡•‡ –‹‘͸ǤʹǤʹǤͳǤͳ‹–Š‡‹–”‘†— –‹‘ȌǤ

Š‡•—‰‰‡•–‹‰–Š‡’”‡• ”‹’–‹‘‘ˆƒ ”‘Ž‹†‡•–‘Š›’‡”–‡•‹˜‡’ƒ–‹‡–•ǡ‹–•Š‘—Ž†„‡ ‡•—”‡†–Šƒ–ƒ’‘••‹„Ž‡’”‡ ‡†‹‰ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡”–”‡ƒ–‡–‹•†‹• ‘–‹—‡†Ǥ ‘„‹‡†ƒ†‹‹•–”ƒ–‹‘‘ˆ–Š‡•‡†”—‰•™‘—Ž†‘–‘Ž›‹–‡”ˆ‡”‡™‹–Š†‹ƒ‰‘•–‹ ˆ‹†Ǧ ‹‰•ǡ„—– ‘—Ž†ƒŽ•‘Ž‡ƒ†–‘•‡˜‡”‡Š›’‘–‡•‹‘†—‡–‘‹ ”‡ƒ•‡†’Žƒ•ƒ ‘ ‡–”ƒ–‹‘• ‘ˆ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡”•ǡ™Š‹ Š–‡†–‘„‡•—„Œ‡ ––‘‡–ƒ„‘Ž‹œƒ–‹‘„›͵Ͷ͵͸ͳǤ Š‡”‡ˆ‘”‡ǡ•–”‹ –‹•–”— –‹‘•ƒ†‡•—”‹‰’ƒ–‹‡– ‘’Ž‹ƒ ‡‹•‹’‘”–ƒ–Ǥ

8.2.2 Comparisonwithpreviousstudies ”‡˜‹‘—•ƒ––‡’–•ƒ––Š‡‹†‡–‹ˆ‹ ƒ–‹‘‘ˆ—–ƒ– ͷ Šƒ‡Ž„Ž‘ ‡”•Šƒ˜‡„‡‡ ƒ†‡Ǥ –Š‡‹”ʹͲͳͶ•–—†›ƒ—„‡”etal.‹†‡–‹ˆ‹‡†‡Ǥ‰Ǥ˜‡”ƒ’ƒ‹Žƒ†ƒ‹Ž‘”‹†‡ƒ•„Ž‘ Ǧ ‡”• ‘ˆ —–ƒ–  ͷ Šƒ‡Ž•ʹͲ͵Ǥ‡˜‡”–Š‡Ž‡••ǡ–Š‡• ‘’‡‘ˆ–Š‡•–—†›™ƒ•— Š •ƒŽŽ‡”ǡ”‡’‘”–‹‰–‡•–•‘Ž‡••–ŠƒʹͲ ‘’‘—†•Ǥ —”–Š‡”‘”‡ǡ–Š‡ˆ‘ —•™ƒ•‘ ͳ͸ͺ‹Š‹„‹–‹‘ǡ™Š‹Ž‡ ͳͷͳ‹Š‹„‹–‹‘™ƒ•‘–‹˜‡•–‹‰ƒ–‡†ˆ‘”‘•–•—„•–ƒ ‡•Ǥ ‡”ƒ’ƒ‹Ž†‹†‹Š‹„‹– ͷͳ͸ͺ Šƒ‡Ž•ƒ–’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ ‘ ‡–”ƒ–‹‘•ǡ™Š‹Ž‡ –Š‡ ͳͷͳƒ†ͳͷͺ—–ƒ–•”‡“—‹”‡†Š‹‰Š‡” ‘ ‡–”ƒ–‹‘•ʹͲ͵Ǥ ‘—”•–—†›ǡ–Š‹• •—„•–ƒ ‡™ƒ•‡Ž‹‹ƒ–‡†ƒ•ƒ ƒ†‹†ƒ–‡‹–Š‡‹‹–‹ƒŽ• ”‡‡†—‡–‘‹–•Ž‹‹–‡†ƒ„‹Ž‹–› –‘„Ž‘  ͷ ͳͷͳǤ‹‹Žƒ”Ž›ǡ‘‡‘ˆ–Š‡‘–Š‡” ‘’‘—†•–‡•–‡†„›ƒ—„‡”etal. ™‡”‡ƒ‘‰–Š‡•—„•–ƒ ‡•‹Š‹„‹–‹‰ ͷ ͳͷͳ™‹–Šε͵͵Ǥ͵Ψ͵ͷʹǤŽƒ–‡”•–—†›†‹•Ǧ Ž‘•‡†–Šƒ––Š‡ ͷͳͶͷ Šƒ‡Ž‹•‘–„Ž‘ ‡†„›˜‡”ƒ’ƒ‹Žǡ™Š‹ Š•—‰‰‡•–•–Šƒ– ’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡• ƒŽƒ”‰‡Ž›˜ƒ”›†‡’‡†‹‰‘–Š‡—–ƒ–‹‘ϯϭϯǤ Š‹„‹–‹‘ ‘ˆ–Š‡™‹Ž†–›’‡™ƒ•ƒŽ•‘‘–‹˜‡•–‹‰ƒ–‡†„›ƒ—„‡”etal.ʹͲ͵Ǥ ‘™‡˜‡”ǡ˜‡”ƒ’ƒ‹Ž‹•ƒ

‘™„Ž‘ ‡”‘ˆŠ —””‡–•‹–Š‡Š‡ƒ”–ǡ™Š‹ Šƒ”‡‰‡‡”ƒ–‡†„› ͷȀ ͵Š‡–Ǧ ‡”‘–‡–”ƒ‡”•ͳͷ͸ǡʹͲͶǤŠ‡”‡ˆ‘”‡ǡ‹– ƒ„‡ƒ••—‡†–Šƒ– ͷ™‹Ž†–›’‡ Šƒ‡Ž•™‹ŽŽ„‡

͸͸ ϴŝƐĐƵƐƐŝŽŶ ƒˆˆ‡ –‡†„›˜‡”ƒ’ƒ‹ŽǤŠ‹•™ƒ•ƒƒ•’‡ –†‡Ž‹„‡”ƒ–‡Ž›‡š Ž—†‡†‹‘—”•–—†›–‘ƒ˜‘‹† —†‡•‹”‡† ƒ”†‹ƒ •‹†‡‡ˆˆ‡ –•ǡ•‹ ‡Ž‘••‘ˆˆ— –‹‘‹ ͷ™‹Ž†–›’‡Šƒ•„‡‡Ž‹‡† –‘Ž‘‰•›†”‘‡ͳͻ͸ǡ͵ͷʹǤ‘–ƒ„Ž›ǡ˜‡”ƒ’ƒ‹ŽŠƒ•„‡‡†‡• ”‹„‡†–‘•Š‘”–‡ǡ”ƒ–Š‡” –Šƒ’”‘Ž‘‰‹–‡”˜ƒŽ•ƒ†–Š—•–‘’”‘–‡ –ˆ”‘ ƒ”†‹ƒ ƒ””Š›–Š‹ƒ•͵͸ʹǡ͵͸͵ǤŠ‹•’”‘Ǧ –‡ –‹˜‡‡ˆˆ‡ –Šƒ•„‡‡•—‰‰‡•–‡†–‘„‡–Š‡”‡•—Ž–‘ˆ‹–•„Ž‘ ƒ‰‡‘ˆǦ–›’‡˜‘Ž–ƒ‰‡Ǧ†‡Ǧ ’‡†‡– ƒŽ ‹— Šƒ‡Ž•͵͸Ͷǡ͵͸ͷǤ  ‘–”ƒ•––‘‘—”•–—†›ǡƒ—„‡”etal.†‹†‘–‹˜‡•–‹Ǧ ‰ƒ–‡–Š‡‹Š‹„‹–‘”›‡ˆˆ‡ –•‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‘”CYP11B2‡š’”‡••‹‘ʹͲ͵ǡ͵ͷʹǤ

8.2.3 Outlook:Futurestudiesofchannelinhibitors —”–Š‡” •–—†‹‡• ƒ”‡ ™ƒ””ƒ–‡† –‘ ‹˜‡•–‹‰ƒ–‡ –Š‡ ‡ˆˆ‡ –• ‘ˆ  ͷ —–ƒ– Šƒ‡Ž „Ž‘ ‡”•‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ† ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘‘”‡ Ž‘•‡Ž›Ǥ ‘™‡˜‡”ǡ–Š‡ Žƒ ‘ˆƒ•—‹–ƒ„Ž‡”‘†‡–‘†‡Žˆ‘”—–ƒ–KCNJ5 ‘’Ž‹ ƒ–‡•invivo•–—†‹‡•ǤKcnj5‹• ‡š’”‡••‡†‹‡‹–Š‡”‘—•‡‘””ƒ–ƒ†”‡ƒŽ‰Žƒ†ƒ†ƒ‰‡‡”ƒ–‡†‘—•‡‘†‡Ž†‹† ‘–”‡’Ž‹ ƒ–‡–Š‡Š—ƒ’Š‡‘–›’‡ʹ͸͵Ȃʹ͸ͷǤ

‘‹˜‡•–‹‰ƒ–‡–Š‡•Š‘”–Ǧ–‡”‡ˆˆ‡ –•‘ˆ”‘š‹–Š”‘› ‹‘ƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•ǡƒŠ—ƒ •–—†›™‘—Ž†„‡ˆ‡ƒ•‹„Ž‡ǡ•‹ ‡–Š‡ƒ–‹„‹‘–‹ ‹•ƒƒ’’”‘˜‡††”—‰‹–Š‡Ǥ‹ ‡ƒŽ†‘•Ǧ –‡”‘‡Šƒ•ƒ•Š‘”–ŠƒŽˆǦŽ‹ˆ‡‘ˆ—†‡”ʹͲ‹—–‡•ǡƒ”‡•’‘•‡‹•‡š’‡ –‡†–‘„‡‡ƒ•—”ƒǦ „Ž‡“—‹ Ž›͵ͷʹǡ͵͸͸Ǥ‘š‹–Š”‘› ‹™‘—Ž†„‡ƒ†‹‹•–‡”‡†–‘’ƒ–‹‡–•ˆ‘”ƒˆ‡™†ƒ›• ƒ†’Žƒ•ƒƒŽ†‘•–‡”‘‡Ž‡˜‡Ž•™‘—Ž†„‡‘‹–‘”‡†Ǥ ’ƒ–‹‡–•‡Ž‹‰‹„Ž‡ˆ‘”—‹Žƒ–‡”ƒŽ ƒ†”‡ƒŽ‡ –‘›ǡ–Š‡‡ƒ•—”‡†”‡•’‘•‡ ‘—Ž†„‡ƒ– Š‡†™‹–Š–Š‡‰‡‘–›’‡‘ˆ–Š‡–—Ǧ ‘”ƒˆ–‡”•—”‰‡”›͵ͷʹǤ

˜‡•–‹‰ƒ–‹‰–Š‡‡ˆˆ‡ –•‘ˆƒ ”‘Ž‹†‡•‘ ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘‹•ƒ„‹‰‰‡” ŠƒŽŽ‡‰‡Ǥ‘‰Ǧ –‡”ƒ†‹‹•–”ƒ–‹‘‘ˆ”‘š‹–Š”‘› ‹–‘’ƒ–‹‡–•™‘—Ž†‘–„‡”‡ ‘‡†ƒ„Ž‡„‡Ǧ ƒ—•‡‹– ‘—Ž†Ž‡ƒ†–‘„ƒ –‡”‹ƒŽ”‡•‹•–ƒ ‡͵ͷʹǤ‡ŽŽ —Ž–—”‡•–—†‹‡•ƒ”‡ ‘’Ž‹ ƒ–‡†ǡ•‹ ‡ ‘˜‡”‡š’”‡••‹‘‘ˆ—–ƒ–KCNJ5”‡†— ‡• ‡ŽŽ˜‹ƒ„‹Ž‹–›ƒ† ƒ ƒ—•‡†‡ƒ–Šƒ•ƒ”‡•—Ž– ‘ˆƒ••‹˜‡‹‘‹ˆŽ—š͵ͳͳǡ͵ͷʹǤŠ‹•‘–‹‘‹•ˆ—”–Š‡”‹ŽŽ—•–”ƒ–‡†„›‹etal.ǡ™Š‘”‡’‘”– –Šƒ– ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘‹ ͳͷ ‡ŽŽ••–ƒ„Ž›–”ƒ•ˆ‡ –‡†™‹–ŠKCNJ5T158A‹•”‡†— ‡† †‡•’‹–‡–Š‡ˆƒ ––Šƒ–ƒ†”‡ƒŽŠ›’‡”’Žƒ•‹ƒŠƒ•„‡‡‘„•‡”˜‡†‹—–ƒ–‹‘ ƒ””‹‡”•in vivoͳͻ͹ǡ͵ͲͻǤ‡†— ‡†˜‹ƒ„‹Ž‹–›†—‡–‘•–”‘‰‹‘‹ˆŽ—š™‘—Ž†‡š’Žƒ‹–Š‹•‡ˆˆ‡ –Ǥ –•Š‘—Ž† „‡‘–‡†–Šƒ––Š‡ƒ—–Š‘”•†‘‘– ‘•‹†‡”–Š‹•‹–‡”’”‡–ƒ–‹‘‹–Š‡†‹• —••‹‘‘ˆ–Š‡‹” ˆ‹†‹‰•͵ͲͻǤŠ‡Ž‹‹–ƒ–‹‘•‘ˆ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡•ƒ•‘†‡Ž•ˆ‘”‘”ƒŽ ‡ŽŽ’”‘Ž‹ˆ‡”ƒǦ –‹‘™‹ŽŽ„‡ˆ—”–Š‡”†‹• —••‡†‹•‡ –‹‘ͺǤ͵ǤͳǤ͵Ǥ

”‹ƒ”› ‡ŽŽ —Ž–—”‡‘ˆ–—‘” ‡ŽŽ•™‘—Ž†„‡ƒ‘–Š‡”•—‹–ƒ„Ž‡ƒ’’”‘ƒ Š–‘‹˜‡•–‹‰ƒ–‡ –Š‡‡ˆˆ‡ –•‘ˆƒ ”‘Ž‹†‡•‘KCNJ5—–ƒ–•Ǥ ‘™‡˜‡”ǡ™Š‹Ž‡•— Šexvivo —Ž–—”‡•

͸͹ ϴŝƐĐƵƐƐŝŽŶ Šƒ˜‡„‡‡—•‡†‹‹˜‡•–‹‰ƒ–‹‘•‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ† ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘‹–Š‡ ’ƒ•–ǡ Ž‹‹–‡† ƒ˜ƒ‹Žƒ„‹Ž‹–›ǡ ŠƒŽŽ‡‰‡• ‹ –Š‡ ‹•‘Žƒ–‹‘ ’”‘ ‡••ƒ†˜ƒ”‹ƒ–‹‘„‡–™‡‡ •ƒ’Ž‡•ˆ”‘†‹ˆˆ‡”‡–’ƒ–‹‡–•‹‰Š– ƒ—•‡†‹ˆˆ‹ —Ž–‹‡•ʹ͸ͺǡ͵͵͵ǡ͵͸͹Ǥ

††‹–‹‘ƒŽŽ›ǡ‡•–ƒ„Ž‹•Š‹‰‘Ǧ”‘†‡–ƒ‹ƒŽ‘†‡Ž•™Š‹ Š”‡•‡„Ž‡–Š‡Š—ƒ’Š‡Ǧ ‘–›’‡‘”‡ Ž‘•‡Ž›‹–‡”•‘ˆƒ†”‡ƒŽKCNJ5‡š’”‡••‹‘‹‰Š–’”‘˜‡—•‡ˆ—Ž–‘–‡•– –Š‡Ž‘‰Ǧ–‡”‡ˆˆ‡ –•‘ˆ”‘š‹–Š”‘› ‹ǤŽ–‡”ƒ–‹˜‡Ž›ǡ‘˜‡Ž‘Ǧƒ–‹„‹‘–‹ ƒ ”‘Ž‹†‡• ™‘—Ž†Šƒ˜‡–‘’ƒ••ƒŽŽ•–ƒ‰‡•ˆ‘”ƒ’’”‘˜ƒŽ„›’Šƒ”ƒ ‡—–‹ ƒŽ”‡‰—Žƒ–‘”›ƒ‰‡ ‹‡•Ǥ

‘ ‘ Ž—†‡ǡ‘—”ˆ‹†‹‰•™‹ŽŽ’‘–‡–‹ƒŽŽ›‹’”‘˜‡–Š‡†‹ƒ‰‘•‹•ƒ†–Š‡–”‡ƒ–‡–‘ˆ •Ǥ‡˜‡”–Š‡Ž‡••ˆ—”–Š‡”inƒ†exvivo•–—†‹‡•ƒ”‡™ƒ””ƒ–‡†‘–Š‡™ƒ›ƒ†‹‰Š– „”‹‰ƒ††‹–‹‘ƒŽŠ—”†Ž‡•Ǥ ˜‡•–‹‰ƒ–‹‘•‘ˆ–Š‡•–”— –—”ƒŽ‹–‡”ƒ –‹‘•„‡–™‡‡ƒ ”‘Ǧ Ž‹†‡•ƒ† ͷ™‘—Ž†ƒŽ•‘„‡‘ˆ‹–‡”‡•–Ǥ

8.3 InvitroinvestigationsoftheeffectsofCACNA1HmutationsonCYP11B2exǦ pressionandaldosteroneproduction • ‘ˆ ›‡–ǡ •‡˜‡”ƒŽ ‰‡”Ž‹‡ —–ƒ–‹‘• ‹ CACNA1H Šƒ˜‡ „‡‡ ‹’Ž‹ ƒ–‡† ‹  ͳͳͷǡͳͳͺǡ͵ʹ͹ȋ ‘’ƒ”‡•‡ –‹‘͸Ǥ͵ǤʹǤʹǤͷ‹–Š‡‹–”‘†— –‹‘ȌǤŠ‡•–—†‹‡•ˆ‡ƒ–—”‡†‹–Š‹• ™‘”‹’”‘˜‡‘—”—†‡”•–ƒ†‹‰‘ˆ–Š‡—†‡”Ž›‹‰‰‡‡–‹ •‘ˆ  ƒ†‰‹˜‡Š‹–• –‘™ƒ”†••—‹–ƒ„Ž‡–”‡ƒ–‡–‘’–‹‘•ǤŠ‡›ƒŽ•‘ƒŽ‡”––‘–Š‡’‹–ˆƒŽŽ•”‡•‡ƒ” Š‡”•‹‰Š– ‡ ‘—–‡”‹‰‡‡–‹ ‹˜‡•–‹‰ƒ–‹‘•‘ˆ Ǥ

8.3.1 CACNA1H M1549V increases aldosterone production and CYP11B2 exǦ pressioninHAC15cells Š‡‰‡”Ž‹‡CACNA1HM1549V—–ƒ–‹‘™ƒ•ˆ‹”•–‹†‡–‹ˆ‹‡†‹’ƒ–‹‡–•™‹–Š‡ƒ”Ž›Ǧ ‘•‡– ƒ†‹• Šƒ”ƒ –‡”‹œ‡†„›‹ ‘’Ž‡–‡’‡‡–”ƒ ‡ǡ‹Ǥ‡Ǥ‘–‡˜‡”›—–ƒ–‹‘ ƒ”Ǧ ”‹‡”†‹•’Žƒ›•–Š‡‡š’‡ –‡†’Š‡‘–›’‡ǤŽ‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ•–—†‹‡•‘ˆ—–ƒ– Šƒ‡Ž• •Š‘™ •Ž‘™‡† ‹ƒ –‹˜ƒ–‹‘ ƒ† ƒ –‹˜ƒ–‹‘ ƒ– ‘”‡ Š›’‡”’‘Žƒ”‹œ‡† ’‘–‡–‹ƒŽ•ͳͳͺǤ Š‡ ʹͲͳ͸”‡’‘”–„›‡‹‡”etal.ˆ‡ƒ–—”‡†‹–Š‹•™‘” ‘’”‹•‡•invitro•–—†‹‡•‘ˆ–Š‡ CACNA1HM1549V—–ƒ–‹‘ ‘†— –‡†‹ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽŽ‹‡•͵Ͷ͸Ǥ—” ‹˜‡•–‹‰ƒ–‹‘••—’’‘”––Š‡•—•’‡ –‡†”‘Ž‡‘ˆ–Š‡—–ƒ–‹‘ƒ•–Š‡ ƒ—•‡‘ˆ  ǡ•‹ ‡ –”ƒ•ˆ‡ –‹‘™‹–ŠCACNA1HM1549VŽ‡ƒ†•–‘ƒ‹ ”‡ƒ•‡‹CYP11B2‡š’”‡••‹‘ƒ† ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ‘’ƒ”‹•‘–‘™‹Ž†–›’‡–”ƒ•ˆ‡ –‡† ‡ŽŽ•͵Ͷ͸ǤŠ‹•‹•–”—‡—Ǧ †‡”—•–‹—Žƒ–‡† ‘†‹–‹‘•ǡ‹‹ ‹‰–Š‡invivo•‹–—ƒ–‹‘‹’ƒ–‹‡–•™‹–Šƒ•—’Ǧ ’”‡••‡†‘•–ƒ —”ƒ–‡Ž›ǡƒ•™‡ŽŽƒ•ƒˆ–‡”•–‹—Žƒ–‹‘™‹–Š‰ Ǥ•‹‹Žƒ”–‡Ǧ †‡ › ƒ„‡‘„•‡”˜‡†™Š‡‡š–”ƒ ‡ŽŽ—Žƒ”Ϊ ‘ ‡–”ƒ–‹‘•ƒ”‡‹ ”‡ƒ•‡†Ǥ –‡”‡•–Ǧ ‹‰Ž›ǡ™Š‹Ž‡„‘–Š™‹Ž†–›’‡ƒ†M1549V–”ƒ•ˆ‡ –‡† ‡ŽŽ•‹ ”‡ƒ•‡–Š‡‹”CYP11B2ƒ†

͸ͺ ϴŝƐĐƵƐƐŝŽŶ ƒŽ†‘•–‡”‘‡’”‘†— –‹‘—’‘•–‹—Žƒ–‹‘ǡ–Š‡”‡Žƒ–‹˜‡‹ ”‡ƒ•‡‹••ƒŽŽ‡”‹ ‡ŽŽ• ƒ”Ǧ ”›‹‰–Š‡—–ƒ–‹‘͵Ͷ͸ȋ•‡ –‹‘͹Ǥ͵ǤʹȌǤ‡‘”‹‰‹ƒŽŽ›ƒ––”‹„—–‡†–Š‹•–‘–Š‡ˆƒ ––Šƒ––Š‡ M1549V—–ƒ–‹‘ƒ†–Š‡‘–Š‡”•–‹—Ž‹‡Šƒ ‡ƒŽ†‘•–‡”‘‡’”‘†— –‹‘˜‹ƒ•‹‹Žƒ” ’ƒ–Š™ƒ›•͵Ͷ͸Ǥ

8.3.1.1 ComparisonofourfindingsonCYP11B2expressionandaldosteroneproǦ ductionwithotherstudies Š‡”‘Ž‡‘ˆ—–ƒ–‹‘•‹ͳ ͳͷͶͻ‹  ™ƒ•ˆ—”–Š‡” ‘ˆ‹”‡†‹ƒ•–—†› „›ƒ‹‹Žetal..Š‡›†‹• ‘˜‡”‡†ƒ‰‡”Ž‹‡CACNA1HM1549I—–ƒ–‹‘‹ƒ’ƒ–‹‡–™‹–Š ‡ƒ”Ž›Ǧ‘•‡– ƒ†Ž‡ƒ”‹‰†‹•ƒ„‹Ž‹–›ͳͳͷǤŽ‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡•ƒ”‡•‹‹Žƒ” –‘CACNA1HM1549Vƒ† ‡ŽŽ —Ž–—”‡‡š’‡”‹‡–• ‘ˆ‹”‹ ”‡ƒ•‡†ƒŽ†‘•–‡”‘‡’”‘Ǧ †— –‹‘ƒ†CYP11B2‡š’”‡••‹‘ǡ„—–‘Ž›ƒˆ–‡”•–‹—Žƒ–‹‘™‹–ŠΪ”‡ˆǤͳͳͷǡͳͳͺǤŠ‡Žƒ––‡” ‘„•‡”˜ƒ–‹‘Šƒ•ƒŽ•‘„‡‡ƒ†‡ˆ‘”‘–Š‡”ͳ —–ƒ–‹‘•™‹–Š†‹ˆˆ‡”‡–‡Ž‡ –”‘Ǧ ’Š›•‹‘Ž‘‰‹ ƒŽ Šƒ”ƒ –‡”‹•–‹ •ͳͳͷǡ͵ʹ͹Ǥ

–‡”‡•–‹‰Ž›ǡ–Š‡”‡“—‹”‡‡–‘ˆΪ–‘•‡‡–Š‡‡ˆˆ‡ –‘ˆ–Š‡—–ƒ–‹‘‹•†‹”‡ –Ž›‘’’‘•‹–‡ –‘ –Š‡ ˆ‹†‹‰• ‘ˆ ‘—” •–—†›Ǥ ‹ ‡ ͳ  ͳͷͶͻ ƒ† ͳͷͶͻ  ƒˆˆ‡ – –Š‡ •ƒ‡ ƒ‹‘ƒ ‹†”‡•‹†—‡ƒ††‹•’Žƒ› ‘’ƒ”ƒ„Ž‡‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡•ǡ•‹‹Žƒ”‡ˆǦ ˆ‡ –• ‘ ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ƒ† CYP11B2 ‡š’”‡••‹‘ ™‘—Ž† „‡ ‡š’‡ –‡† –‘ „‡ ˆ‘—†‹invitro‹˜‡•–‹‰ƒ–‹‘•‘ˆ–Š‡•‡—–ƒ–‹‘•ǤŠ‡‡š’Ž‘”‹‰’‘••‹„Ž‡”‡ƒ•‘• ˆ‘”–Š‡‘„•‡”˜‡††‹˜‡”‰‡ ‡ǡ‹–•Š‘—Ž†„‡–ƒ‡‹–‘ƒ ‘—––Šƒ–ƒ–‡†‡ ›–‘™ƒ”†• ƒ ‹ ”‡ƒ•‡ ‹ CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ‡ŽŽ•–”ƒ•ˆ‡ –‡† ™‹–ŠCACNA1HM1549I‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ ƒ„‡’‡” ‡‹˜‡†™‹–Š‘—–’”‹‘” •–‹—Žƒ–‹‘‹–Š‡•–—†›„›ƒ‹‹Žetal.ͳͳͷǤŠ‹Ž‡–Š‡†‹ˆˆ‡”‡ ‡‹–Š‡’”‡•‡–‡††ƒ–ƒ Ž‹‡•™‹–Š‹–Š‡ƒ”‰‹‘ˆ‡””‘”ǡ‹ ”‡ƒ•‡†•ƒ’Ž‡•‹œ‡‹‰Š–’”‘˜‹†‡•‹‰‹ˆ‹ ƒ–”‡•—Ž–• —†‡”„ƒ•ƒŽ ‘†‹–‹‘•ǡƒ‹‰–Š‡”‡“—‹”‡‡–ˆ‘”Ϊ•–‹—Žƒ–‹‘‘„•‘Ž‡–‡Ǥ

‘™‡˜‡”ǡ†‹ˆˆ‡”‡ ‡•‹‡š’‡”‹‡–ƒŽ•‡–—’•‹‰Š–ƒŽ•‘ ‘–”‹„—–‡–‘–Š‡‘„•‡”˜‡††‹Ǧ ˜‡”‰‡ ‡ǣ ‹”•–ǡ†‹ˆˆ‡”‡– ʹͻͷǦ†‡”‹˜‡† ‡ŽŽŽ‹‡•™‡”‡ Š‘•‡ˆ‘”–Š‡‹˜‡•–‹‰ƒ–‹‘‘ˆ ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ ƒ† CYP11B2 ‡š’”‡••‹‘ǡ ™Š‹ Š ‹‰Š– †‹ˆˆ‡” ‹ Ž‡˜‡Ž• ‘ˆ CYP11B2‡š’”‡••‹‘ǡƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ•™‡ŽŽƒ•”‡•’‘•‡–‘‰ ͵ͶͶǤ‡ ‘†ǡ †‹ˆˆ‡”‡––”ƒ•ˆ‡ –‹‘‡–Š‘†•™‡”‡—•‡†ǣŠ‹Ž‡™‡–”ƒ•ˆ‡ –‡†–Š‡ ‡ŽŽ•˜‹ƒ‡Ž‡ –”‘Ǧ ’‘”ƒ–‹‘ǡƒ‹‹Žetal.—•‡†ƒ Š‡‹ ƒŽ–”ƒ•ˆ‡ –‹‘‡–Š‘†ͳͳͷǡ͵Ͷ͸ǤŠ‹•‹‰Š–”‡•—Ž–‹ †‹ˆˆ‡”‡ ‡•‹–”ƒ•ˆ‡ –‹‘‡ˆˆ‹ ‹‡ ›ƒ† ‡ŽŽ˜‹ƒ„‹Ž‹–›Ǥ –‹•’‘••‹„Ž‡–Šƒ––Š‡‡š’‡”‹Ǧ ‡–ƒŽ•‡–—’ Š‘•‡„›ƒ‹‹Žetal.”‡Ž‹‡•‘ƒ•›‡”‰‹•–‹ ‡ˆˆ‡ –‘ˆ–Š‡–”ƒ•ˆ‡ –‡†Ǧ

͸ͻ ϴŝƐĐƵƐƐŝŽŶ –›’‡ Šƒ‡Ž•ƒ†‡†‘‰‡‘—•Ǧ–›’‡ Šƒ‡Ž•ƒ –‹˜ƒ–‡†„›Ϊ•–‹—Žƒ–‹‘Ǥ–‹—ŽƒǦ –‹‘™‹–Š‰ ǡ‘ˆ–‡†‡• ”‹„‡†–‘ƒ‹Ž›ƒ –‹˜ƒ–‡Ǧ–›’‡ Šƒ‡Ž•ǡ†‘‡•‘–ƒ’’‡ƒ”–‘ ’”‘˜‹†‡–Š‹•‡ˆˆ‡ –ʹ͵ǡͳͳͷǤ‘–”ƒ•–‹‰Ž›ǡƒš‹—Ž‡˜‡Ž•‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ† CYP11B2‡š’”‡••‹‘‹‰Š–Šƒ˜‡„‡‡”‡ƒ Š‡†ƒŽ”‡ƒ†›‹—–ƒ– ‡ŽŽ•ƒ––Š‡‰‹˜‡‘˜‡”Ǧ ‡š’”‡••‹‘”ƒ–‡•‹‘—”•–—†›ǤŽ–‡”ƒ–‹˜‡Ž›ǡ•–”‘‰‹‘‹ˆŽ—š–Š”‘—‰Š—–ƒ– Šƒ‡Ž• ‹‰Š–ƒˆˆ‡ – ‡ŽŽ˜‹ƒ„‹Ž‹–›‹—–ƒ– ‡ŽŽ•‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡ƒ– ‘’ƒ”ƒ„Ž‡ –”ƒ•ˆ‡ –‹‘‡ˆˆ‹ ‹‡ ‹‡•ǤŠ‹•‹‰Š–„‡‡•’‡ ‹ƒŽŽ›”‡Ž‡˜ƒ–‹ ‡ŽŽ•–”ƒ•ˆ‡ –‡†„›ƒ”‡ŽǦ ƒ–‹˜‡Ž›Šƒ”•Š‡–Š‘†ǡ•— Šƒ•‡Ž‡ –”‘’‘”ƒ–‹‘Ǥ‘™‡”˜‹ƒ„‹Ž‹–›‹—–ƒ– ‡ŽŽ•ǡ‡‰ƒǦ –‹˜‡Ž›ƒˆˆ‡ –‹‰ ‡ŽŽˆ— –‹‘ƒ•ƒ™Š‘Ž‡ǡ ‘—Ž†–Š‡”‡†— ‡”‡•’‘•‡–‘ˆ—”–Š‡”•–‹—ŽƒǦ –‹‘‹ ‘’ƒ”‹•‘–‘–Š‡™‹Ž†–›’‡Ǥ

‡˜‡”ƒŽ•–—†‹‡•ƒƒŽ›œ‹‰—–ƒ– ͷ Šƒ‡Ž••Š‘™–Šƒ–•–”‘‰‹‘‹ˆŽ—š‹•ƒ„Ž‡–‘ ”‡†— ‡˜‹ƒ„‹Ž‹–›ƒ†’”‘Ž‹ˆ‡”ƒ–‹‘‹–”ƒ•ˆ‡ –‡† ‡ŽŽ•ȋ ‘’ƒ”‡ ͵Ͳͻǡ͵ͳͳǡ͵ͷʹƒ†•‡ –‹‘ ͺǤʹǤ͵ȌǤ‹Ž†‡”–”ƒ•ˆ‡ –‹‘‡–Š‘†‘”ƒƒ”‡†Ž›Ž‘™‡”–”ƒ•ˆ‡ –‹‘”ƒ–‡™‘—Ž†ƒ˜‘‹† ‘”ƒ–Ž‡ƒ•–ƒ––‡—ƒ–‡–Š‡•‡‡ Šƒ‹••ƒ†’‘••‹„Ž›ƒŽŽ‘™ˆ‘”•›‡”‰‹•–‹ ‡ˆˆ‡ –•‘ˆΪ ƒ†–Š‡—–ƒ–‹‘‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Ǥ‘ ‘ Ž—†‡ǡ–Š‡•‡‡‹‰Ž› ‘–”ƒ†‹ –‘”› ˆ‹†‹‰•‘–Š‡‡ˆˆ‡ –•‘ˆ•–‹—Žƒ–‘”•‘ˆƒŽ†‘•–‡”‘‡’”‘†— –‹‘‘CACNA1H—–ƒ–Ǧ –”ƒ•ˆ‡ –‡† ‡ŽŽ• ƒŽ‹‡Ž›„‡”‡ ‘ ‹Ž‡†„› ‘•‹†‡”‹‰•–ƒ–‹•–‹ ƒŽ’‘™‡”ƒ†’”‘ ‡Ǧ †—”ƒŽ†‹ˆˆ‡”‡ ‡•‘ˆ–Š‡–™‘•–—†‹‡•Ǥ

8.3.1.2 CACNA1HM1549VcanbeinhibitedbyTǦtypechannelblockermibefradil ‘—”•–—†›ǡ™‡ƒŽ•‘‹˜‡•–‹‰ƒ–‡†–Š‡‡ˆˆ‡ –•‘ˆ–Š‡Ǧ–›’‡ Šƒ‡Ž‹Š‹„‹–‘”‹„‡ˆ”ƒ†‹Žǡ ™Š‹ Š’”‡˜‡–•ƒʹΪ‹ˆŽ—š–Š”‘—‰Šͳ  Šƒ‡Ž•ͳʹͷǣŠ‡ ‘’‘—†•‹‰‹ˆ‹ ƒ–Ž› ”‡†— ‡†„‘–ŠCYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ‡ŽŽ•‘˜‡”‡š’”‡••‹‰ CACNA1H™‹Ž†–›’‡ƒ†M1549VǤ ‘™‡˜‡”ǡ—’‘‹Š‹„‹–‘”–”‡ƒ–‡–ƒŽ†‘•–‡”‘‡’”‘Ǧ †— –‹‘™ƒ••–‹ŽŽ‡Ž‡˜ƒ–‡†‹CACNA1HM1549VǦ–”ƒ•ˆ‡ –‡† ‡ŽŽ•‹ ‘’ƒ”‹•‘–‘–Š‡ ™‹Ž†–›’‡ǡ™Š‹Ž‡–Š‡”‡™ƒ•‘†‹ˆˆ‡”‡ ‡‘„•‡”˜‡†‹CYP11B2‡š’”‡••‹‘͵Ͷ͸ȋ•‡ –‹‘ ͹Ǥ͵ǤʹȌǤ‡ƒ––”‹„—–‡†–Š‹•†‹˜‡”‰‡ ‡–‘–Š‡•Š‘”–ŠƒŽˆǦŽ‹ˆ‡‘ˆCYP11B2‹ ‘Ǧ ’ƒ”‹•‘–‘–Š‡”‡Žƒ–‹˜‡Ž›Š‹‰Š•–ƒ„‹Ž‹–›‘ˆƒŽ†‘•–‡”‘‡͵Ͷ͸ǡ͵͸ͺǡ͵͸ͻǤ ‡ ‡ǡ”‡•‹†—ƒŽ‡Ž‡˜ƒ–‡† Š‘”‘‡Ž‡˜‡Ž•ˆ”‘„‡ˆ‘”‡–Š‡‹Š‹„‹–‘”‡š‡”–‡†‹–•ˆ—ŽŽ‡ˆˆ‡ –‘ƒŽ†‘•–‡”‘‡’”‘†— Ǧ –‹‘™‘—Ž†•–‹ŽŽ„‡‡ƒ•—”ƒ„Ž‡˜‹ƒ ǡ™Š‹Ž‡CYP11B2‡š’”‡••‹‘™‘—Ž†”‡’”‡•‡– –Š‡‘”‡”‡ ‡–•‹–—ƒ–‹‘‹–Š‡ ‡ŽŽƒˆ–‡”–Š‡ˆ—ŽŽ‡ˆˆ‡ –‘ˆ–Š‡‹Š‹„‹–‘”Šƒ•ƒŽ”‡ƒ†›„‡‡ ”‡ƒ Š‡†Ǥ ‹”•–ǡ–Š‡‘„•‡”˜‡†‡ˆˆ‡ –•‘ˆ‹„‡ˆ”ƒ†‹Ž•—„•–ƒ–‹ƒ–‡–Šƒ––Š‡‹ ”‡ƒ•‡•‹ƒŽǦ †‘•–‡”‘‡’”‘†— –‹‘ƒ†CYP11B2‡š’”‡••‹‘‹‘—”•–—†›™‡”‡‹†‡‡†–Š‡’”‘†— – ‘ˆǦ–›’‡ Šƒ‡Žˆ— –‹‘Ǥ‡ ‘†ǡ–Š‡›†‡‘•–”ƒ–‡–Šƒ–CACNA1HM1549V—–ƒ–

͹Ͳ ϴŝƐĐƵƐƐŝŽŶ Šƒ‡Ž•ƒ”‡•–‹ŽŽ•—• ‡’–‹„Ž‡–‘’Šƒ”ƒ ‘Ž‘‰‹ ƒŽǦ–›’‡ Šƒ‡Ž‹Š‹„‹–‹‘ǤŠ‹•‹†‹Ǧ ƒ–‡•–Šƒ–Ǧ–›’‡ Šƒ‡Ž„Ž‘ ‡”•‹‰Š– ‘•–‹–—–‡ƒ•—‹–ƒ„Ž‡–”‡ƒ–‡–‘’–‹‘‹’ƒǦ –‹‡–•™‹–Š  Ǥ ‘™‡˜‡”ǡ‹„‡ˆ”ƒ†‹Ž‹•‘–ƒ‡Ž‹‰‹„Ž‡ Š‘‹ ‡ǡ•‹ ‡‹–™ƒ•”‡–”ƒ –‡† ˆ”‘–Š‡ƒ”‡–†—‡–‘•‡˜‡”‡†”—‰‹–‡”ƒ –‹‘•ͳʹͻǤ

‘’‘—†•ƒ Š‹‡˜‹‰ƒ”‡Žƒ–‹˜‡Ž›•‡Ž‡ –‹˜‡„Ž‘ ƒ‰‡‘ˆŽ‘™˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡Ž•‘˜‡”Š‹‰Š˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡†‘‡•ƒ”‡”ƒ”‡ȋˆ‘””‡˜‹‡™ ‘’ƒ”‡͵͹ͲȌǤ ‘™‡˜‡”ǡ ™Š‹Ž‡ƒ› ƒŽ ‹—ƒ–ƒ‰‘‹•–•ˆ”‡“—‡–Ž›’”‡• ”‹„‡†ƒ•ƒ–‹Š›’‡”–‡•‹˜‡•’”‹ƒ”‹Ž› ƒ –‘Ǧ–›’‡ Šƒ‡Ž•ǡ•‘‡ ƒƒŽ•‘„Ž‘ Ǧ–›’‡ Šƒ‡Ž•ƒ–‹ ”‘‘Žƒ” ‘ ‡–”ƒǦ –‹‘• ȋˆ‘” ”‡˜‹‡™ ‘’ƒ”‡ ͻ͹ǡ͵͹ͲȌǤ —”–Š‡”‘”‡ǡ –Š‡ †”—‰ ‡ˆ‘‹†‹’‹‡ǡ —””‡–Ž› ƒ’Ǧ ’”‘˜‡†‹ ƒ’ƒǡ‹•ƒ†—ƒŽǦ–›’‡ƒ†Ǧ–›’‡ Šƒ‡Ž„Ž‘ ‡”–Šƒ–Šƒ•„‡‡•Š‘™–‘ ‡ˆˆ‡ –‹˜‡Ž› ”‡†— ‡ ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ in vitroƒ•™‡ŽŽƒ•‹Š—ƒ–‡•–•—„Ǧ Œ‡ –•ͳͶͳǡʹʹͻǡ͵͹ͳǡ͵͹ʹǤ ƒ††‹–‹‘ǡ–Š‡‡ˆ‘‹†‹’‹‡ȋǦȌ‹•‘‡”•‡‡•–‘„‡ƒ•‡Ž‡ –‹˜‡‹Š‹„Ǧ ‹–‘”‘ˆǦ–›’‡ Šƒ‡Ž•ƒ†‹–•ƒ„‹Ž‹–›–‘„Ž‘ ͳ  Šƒ‡Ž•Šƒ•„‡‡ ‘Ǧ ˆ‹”‡†͵͹͵ǡ͵͹ͶǤ

‹ ‡–Š‡‹ˆ‘”ƒ–‹˜‡˜ƒŽ—‡‘ˆ ‡ŽŽ —Ž–—”‡•–—†‹‡•‹–Š‡ƒ••‡••‡–‘ˆ–”‡ƒ–‡–‘’Ǧ –‹‘•‹•Ž‹‹–‡†ǡƒƒ‹ƒŽ‘†‡Ž‹‰Š–Š‡Ž’–‘‡š’Ž‘”‡ ƒŽ ‹— Šƒ‡Ž„Ž‘ ‡”•ƒ• –”‡ƒ–‡–‘’–‹‘•ˆ‘”’ƒ–‹‡–•™‹–Š  ǤCACNA1H‹•‡š’”‡••‡†‹–Š‡—”‹‡ ǡ ™Š‹ Š‹‰Š–ƒ‡–Š‡‘—•‡ƒ•—‹–ƒ„Ž‡‘†‡Ž‘”‰ƒ‹•͸͵Ǥ

8.3.1.3 Outlook:InvestigatingtheeffectsofCACNA1HM1549VoncellproliferaǦ tion –Š‹••–—†›ǡ™‡‘Ž›‹˜‡•–‹‰ƒ–‡†•Š‘”––‡”‡ˆˆ‡ –•‘ˆ–Š‡CACNA1HM1549V—–ƒ–‹‘ ‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†CYP11B2‡š’”‡••‹‘invitro͵Ͷ͸Ǥ‹ ”‘‘†—Žƒ”ƒ†”‡ƒŽ Š›’‡”’Žƒ•‹ƒŠƒ•„‡‡‘„•‡”˜‡†‹‘‡  ’ƒ–‹‡–™Š‘—†‡”™‡–ƒ†”‡ƒŽ‡ –‘›Ǥ ‘†—Ž‡• ™‡”‡ ’‘•‹–‹˜‡ ˆ‘” –Š‡ ‡š’”‡••‹‘ ‘ˆ ͳ ͳͳͺǤŠ‹•’‘•‡•–Š‡“—‡•–‹‘ ™Š‡–Š‡”ͳ ͳͷͶͻ‹‰Š–ƒŽ•‘’”‘‘–‡ ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘‘”’”‡˜‡– ‡ŽŽ†‡ƒ–ŠǤ –Š‡’ƒ•–ǡ–Š‡ƒ–‹’”‘Ž‹ˆ‡”ƒ–‹˜‡‡ˆˆ‡ –•‘ˆ‹„‡ˆ”ƒ†‹ŽŽ‡†–‘–Š‡ ‘ Ž—•‹‘–Šƒ–ƒʹΪ ‹ˆŽ—š–Š”‘—‰ŠǦ–›’‡˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž•‹‰Š–„‡Ž‹‡†–‘ ‡ŽŽ’”‘Ž‹ˆ‡”ƒǦ –‹‘͵͹ͷǡ͵͹͸Ǥ ‘™‡˜‡”ǡ–Š‡•‡ƒ••—’–‹‘•™‡”‡ ŠƒŽŽ‡‰‡†—’‘–Š‡†‹• ‘˜‡”›‘ˆ•‡˜‡”ƒŽ ‘ˆˆǦ–ƒ”‰‡–‡ˆˆ‡ –•‘ˆ–Š‡ ‘’‘—†ͻ͹ǡ͵͹͹Ǥ‘–— Š‹• —””‡–Ž›‘™ƒ„‘—––Š‡”‘Ž‡‘ˆ Ǧ–›’‡ Šƒ‡Ž•‹ƒ†”‡ƒŽ ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘ƒ†‰”‘™–Šȋ ‘’ƒ”‡ͳͳͲȌǤ

– •Š‘—Ž† „‡ ‘–‡† –Šƒ– ‡ŽŽ —Ž–—”‡ •–—†‹‡• ‹˜‡•–‹‰ƒ–‹‰ –Š‡ ‹’ƒ – ‘ˆ ͳ  ͳͷͶͻ‘ƒ†”‡ƒŽ’”‘Ž‹ˆ‡”ƒ–‹‘‹‰Š–Šƒ˜‡•‡˜‡”ƒŽŽ‹‹–ƒ–‹‘•Ǥ ‡‡”ƒŽŽ›ǡ ‘–‹—‘—• ƒ ‡” ‡ŽŽŽ‹‡•ƒ”‡‘ˆ–‡‰‡‡”ƒ–‡†ˆ”‘ˆƒ•–‰”‘™‹‰–—‘”•͵͹ͺǤ ‘’ƒ”‹•‘‘ˆ ‡ŽŽ

͹ͳ ϴŝƐĐƵƐƐŝŽŶ Ž‹‡•™‹–Š–—‘” ‡ŽŽ•ƒ† ‡ŽŽ•ˆ”‘‘”ƒŽ–‹••—‡‘”‹‰‹ƒ–‹‰ˆ”‘•‹š†‹ˆˆ‡”‡––‹••—‡ –›’‡• ‘˜‡›‡†ˆ”‡“—‡–ƒŽ–‡”ƒ–‹‘•‹‰‡‡•‹˜‘Ž˜‡†‹–Š‡ ‡ŽŽ › Ž‡͵͹ͻǤŠ‡•‡ˆ‹†Ǧ ‹‰• ŠƒŽŽ‡‰‡–Š‡‘–‹‘–Šƒ–ƒƒ —”ƒ–‡”‡’”‡•‡–ƒ–‹‘‘ˆ‘”ƒŽ’”‘Ž‹ˆ‡”ƒ–‹‘ ƒ „‡ƒ Š‹‡˜‡†„›–Š‡—•‡‘ˆ ƒ ‡” ‡ŽŽŽ‹‡•ǡ™Š‹ Š™‘—Ž†„‡†‡•‹”‡†–‘‹˜‡•–‹‰ƒ–‡–Š‡ ’”‘Ž‹ˆ‡”ƒ–‹˜‡‡ˆˆ‡ –•‘ˆƒ—–ƒ–‹‘‹‡‹–Š‡”‘”ƒŽ‘”„‡‹‰–—‘”–‹••—‡Ǥ‡˜‡”–Š‡Ǧ Ž‡••ǡ ʹͻͷ ‡ŽŽ•Šƒ˜‡„‡‡—•‡†–‘•–—†› ‡ŽŽ‰”‘™–Šƒ†’”‘Ž‹ˆ‡”ƒ–‹‘‹–Š‡’ƒ•–Ǥ ‘™‡˜‡”ǡ –Š‡•‡ •–—†‹‡• ™‡”‡ ‘ˆ–‡ –ƒ”‰‡–‡†ƒ– –Š‡ Šƒ”ƒ –‡”‹œƒ–‹‘ ‘” –”‡ƒ–‡– ‘ˆ ƒ†”‡‘ ‘”–‹ ƒŽ ƒ ‡”ȋ ‘’ƒ”‡ ͵͵ʹǡ͵͵͵ȌǤ ƒ††‹–‹‘–‘ƒ†”‡‘ ‘”–‹ ƒŽ ƒ” ‹‘ƒ ‡ŽŽ Ž‹‡•ǡ’”‹ƒ”› ‡ŽŽ•ˆ”‘ƒ‹ƒŽ•Šƒ˜‡„‡‡—•‡†–‘•–—†›ƒ†”‡ƒŽ’”‘Ž‹ˆ‡”ƒ–‹‘ȋ ‘Ǧ ’ƒ”‡‡Ǥ‰Ǥ͵ͺͲȌǤ ‘™‡˜‡”ǡ–Š‡•‡ ‡ŽŽ•Šƒ˜‡ƒŽ‹‹–‡†Ž‹ˆ‡•’ƒƒ†–Š‡‹”’”‘’‡”–‹‡•‹‰Š– Šƒ‰‡‘˜‡”–‹‡ǤŠ‡”‡ˆ‘”‡ǡ–Š‡‹”—•‡”‡“—‹”‡• ‘•–ƒ–•—’’Ž›™‹–Šˆ”‡•Š–‹••—‡ƒ† ‹•‘Žƒ–‹‘‘ˆ–Š‡†‡•‹”‡† ‡ŽŽ•ȋ ‘’ƒ”‡͵͵ʹǡ͵͵͵ȌǤ ƒ††‹–‹‘ǡ–Š‡›‹‰Š–’”‘˜‡†‹ˆˆ‹ —Ž––‘ –”ƒ•ˆ‡ –ȋ ‘’ƒ”‡‡Ǥ‰Ǥ͵ͺͳȌǤ

Š‡‡š’”‡••‹‘•›•–‡ƒŽ•‘’‘•‡•’”‘„Ž‡•ǣƒ••‹˜‡‹‘‹ˆŽ—š ”‡ƒ–‡†„›‘˜‡”‡š’”‡•Ǧ •‹‘‘ˆ—–ƒ–‹‘ Šƒ‡Ž•‹‰Š–ƒŽ”‡ƒ†›ƒˆˆ‡ – ‡ŽŽ˜‹ƒ„‹Ž‹–›ǡƒ•‹‰‘–Š‡”‡ˆˆ‡ –• ȋ ‘’ƒ”‡•‡ –‹‘•ͺǤ͵ǤͳǤͳƒ†ͺǤʹǤ͵ȌǤŠ‡”‡ˆ‘”‡ǡƒƒ‹ƒŽ‘†‡Ž‹‰Š–’”‘˜‡ƒ‘”‡ •—‹–ƒ„Ž‡–‘‘Ž–‘‹˜‡•–‹‰ƒ–‡–Š‡‡ˆˆ‡ –•‘ˆCACNA1HM1549V‘ ‡ŽŽ’”‘Ž‹ˆ‡”ƒ–‹‘ǤŠ‡•‡ ƒ‹ƒŽ• ‘—Ž†„‡‡’–ˆ‘”ƒ‡š–‡†‡†’‡”‹‘†‘ˆ–‹‡ƒ†ƒ†”‡ƒŽ• ‘—Ž†„‡• ”‡‡‡† ˆ‘”Š›’‡”’Žƒ•‹ƒƒˆ–‡”†‡ƒ–ŠǤ˜‹”‘‡–ƒŽˆƒ –‘”•™Š‹ Š‹‰Š–ƒˆˆ‡ ––Š‡†‡˜‡Ž‘’‡– ‘”•‡˜‡”‹–›‘ˆ ƒ†Š›’‡”’Žƒ•‹ƒǡ•— Šƒ••ƒŽ–‹–ƒ‡ǡ ‘—Ž†ƒŽ•‘„‡‘‹–‘”‡†‹–Š‹• ‡š’‡”‹‡–ǤŠ‹•‹‰Š–Š‡Ž’–‘—†‡”•–ƒ†‡˜‹”‘‡–ƒŽˆƒ –‘”• ‘–”‹„—–‹‰–‘‹Ǧ ‘’Ž‡–‡’‡‡–”ƒ ‡‘ˆ–Š‡—–ƒ–‹‘Ǥ

‡•’‹–‡–Š‡ˆƒ ––Šƒ–‘—”•–—†‹‡•‘ˆ–Š‡CACNA1HM1549V˜ƒ”‹ƒ–Šƒ˜‡•—„•–ƒ–‹ƒ–‡† ‹–•”‘Ž‡‹  ƒ†Šƒ˜‡’”‘˜‹†‡†‹•‹‰Š–‹–‘’Šƒ”ƒ ‘Ž‘‰‹ ƒŽ‘’–‹‘•ǡˆ—”–Š‡”‹Ǧ †‡’–Š•–—†‹‡•ƒ”‡‡‡†‡†ǤŠ‡•‡•Š‘—Ž†‹ Ž—†‡–Š‡Ž‘‰–‡”•–—†›‘ˆƒ‹ƒŽ‘†‡Ž• ƒ””›‹‰–Š‡—–ƒ–‹‘Ǥ

8.3.2 CACNA1HS1073CdoesnotaffectaldosteroneproductionandCYP11B2exǦ pressioninHAC15cells Š‹Ž‡invitro‹˜‡•–‹‰ƒ–‹‘•‘ˆCACNA1HM1549V•—’’‘”–‹–•”‘Ž‡‹  ǡ•‹‹Žƒ”•–—†Ǧ ‹‡•‘ˆ–Š‡S1073C—–ƒ–‹‘†‘‘–”‡˜‡ƒŽƒ›‡ˆˆ‡ –‘ˆ–Š‡—–ƒ–‹‘‘ Šƒ‡Žˆ— –‹‘ ‘”ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ȋ•‡ –‹‘͹ǤͶǤ͵ǡ ‹‰—”‡ͺȌǤŠ‹•‹†‹ ƒ–‡•–Šƒ–‹–‹•‘•–Ž‹‡Ž› ‘––Š‡’”‹ƒ”› ƒ—•‡‘ˆ ‹–Š‡ˆƒ‹Ž›‹–™ƒ•†‹• ‘˜‡”‡†‹Ǥ

͹ʹ ϴŝƐĐƵƐƐŝŽŶ 8.3.2.1 Sequenceconservationandstructuralconsiderations ‹‰Š ‘•‡”˜ƒ–‹‘ ƒ ”‘•• ‘”–Š‘Ž‘‰—‡• ƒ† ’ƒ”ƒŽ‘‰—‡•ǡ ƒ• ‘„•‡”˜‡† ˆ‘” ͳ  ͳͷͶͻ ƒ† –Š‡ •—””‘—†‹‰ ”‡•‹†—‡•ǡ ƒ •‡”˜‡ ƒ• ƒ ‹†‹ ƒ–‘” ‘ˆ –Š‡ ”‡‰‹‘ǯ• ‹Ǧ ’‘”–ƒ ‡‹’”‘–‡‹ˆ— –‹‘ͳͳͺǤŠ‡ͳ ͳͲ͹͵”‡•‹†—‡‹•‘–•–”‘‰Ž› ‘•‡”˜‡† ƒ ”‘•••’‡ ‹‡•ǤŽ›‘–Š‡”’”‹ƒ–‡• ƒ””›ƒ•‡”‹‡‹–Š‡ ‘””‡•’‘†‹‰’‘•‹–‹‘ǡ™Š‹Ž‡ ‘–Š‡”ƒ‹ƒŽ•ǡ‹ Ž—†‹‰ƒ˜ƒ”‹‡–›‘ˆƒƒŽ•ǡ ƒ””›ƒ’”‘Ž‹‡”‡•‹†—‡Ǥ ‘™‡˜‡”ǡ–Š‡ •—””‘—†‹‰”‡‰‹‘ƒ’’‡ƒ”•–‘„‡ƒ–Ž‡ƒ•–‹’ƒ”– ‘•‡”˜‡†ȋ ‘’ƒ”‡ ‹‰—”‡ͻȌǤŠ‹• ‹‰Š–Š‹–ƒ–ƒ‡š‹•–‹‰ǡ„—–‘–˜‡”›•–”‹‰‡–•‡“—‡ ‡Ǧˆ— –‹‘”‡Žƒ–‹‘•Š‹’‘ˆ–Š‹• ”‡‰‹‘ǤŠ‹Ž‡–Š‡”‡•‹†—‡ ‘””‡•’‘†‹‰–‘ͳ ͳͷͶͻ‹• ‘•‡”˜‡†ƒ ”‘••†‹ˆǦ

ˆ‡”‡–Ž‘™˜‘Ž–ƒ‰‡Ǧƒ –‹˜ƒ–‡† ƒŽ ‹— Šƒ‡ŽȽͳ•—„—‹–•ǡͳ ͳͲ͹͵‹•‘–Ǥ‡•Ǧ ‹†—‡••—””‘—†‹‰ͳ ͳͲ͹͵†‘‘–•Š‘™ƒ›Š‘‘Ž‘‰›–‘‘–Š‡” Žƒ••‡•‘ˆ˜‘Ž–Ǧ

ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡ŽȽͳ•—„—‹–•‡‹–Š‡”ȋ ‘’ƒ”‡ ‹‰—”‡ͻȌǤ

Š‡ͳ ͳͲ͹͵—–ƒ–‹‘‹•Ž‘ ƒ–‡†‹–Š‡Ž‹‡”„‡–™‡‡•‡‰‡–• ͸ƒ† ͳȋ ‹‰—”‡͹ȌǤŠ‹•”‡‰‹‘‹•‹˜‘Ž˜‡†‹ Šƒ‡Ž‘†—Žƒ–‹‘„›ƒ˜ƒ”‹‡–›‘ˆ•‡ ‘† ‡••‡‰‡”•ȋˆ‘””‡˜‹‡™•‡‡͵ͺʹȌǤ—–ƒ–‹‘•‹–Š‹•”‡‰‹‘Šƒ˜‡„‡‡†‹• ‘˜‡”‡†‹’ƒǦ –‹‡–•™‹–Š‡’‹Ž‡’•›ǤŠ‹Ž‡–Š‡ͳͲͷͻ—–ƒ–‹‘ƒ’’‡ƒ”•–‘‡†‹ƒ–‡ƒŽ‘••‘ˆͳ  Šƒ‡Žˆ— –‹‘ǡ‘–Š‡”—–ƒ–‹‘•ˆ‘—†‹–Š‹•”‡‰‹‘Šƒ˜‡„‡‡ˆ‘—†‘––‘ Šƒ‰‡ Šƒ‡Ž Šƒ”ƒ –‡”‹•–‹ •͵ͺ͵Ǥ ‘–Š‡” —–ƒ–‹‘ ‹ –Š‹• ”‡‰‹‘ǡ ͳ  ͳͲ͸Ͷǡ Šƒ• „‡‡‹’Ž‹ ƒ–‡†‹ ͵ʹ͹. ‘™‡˜‡”ǡ–Š‡‡˜‹†‡ ‡•—’’‘”–‹‰–Š‡”‘Ž‡‘ˆ–Š‹•—–ƒ–‹‘ ƒ•–Š‡ ƒ—•‡‘ˆ ‹•Ž‡•• ‘’‡ŽŽ‹‰–Šƒˆ‘”—–ƒ–‹‘•‹ͳ ͳͷͶͻǤ‹‹Žƒ” –‘–Š‡”‡•—Ž–•ˆ‘—†‹‘—”•–—†›‘ͳ ͳͲ͹͵ǡ‡Ž‡ –”‘’Š›•‹‘Ž‘‰‹ ƒŽ’”‘’‡”–‹‡• †‹†‘–”‡˜‡ƒŽƒ›†‹ˆˆ‡”‡ ‡„‡–™‡‡™‹Ž†–›’‡ƒ†—–ƒ– Šƒ‡Ž•Ǥ —”–Š‡”‘”‡ǡ ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ƒ†CYP11B2‡š’”‡••‹‘†‹†‘Ž›†‹ˆˆ‡”„‡–™‡‡™‹Ž†–›’‡ƒ† —–ƒ– ‡ŽŽ•—’‘•–‹—Žƒ–‹‘™‹–ŠΪǡ„—–‘–ƒ–„ƒ•ƒŽ ‘†‹–‹‘•͵ʹ͹ǤŠ‡Žƒ––‡”‘„•‡”Ǧ ˜ƒ–‹‘‹•‹Ž‹‡™‹–Š–Š‡’”‡˜‹‘—•Ž›†‹• —••‡†•–—†›„›ƒ‹‹ŽetalǤͳͳͷȋ ‘’ƒ”‡•‡ –‹‘ ͺǤ͵ǤͳǤͳȌǤ

8.3.2.2 Limitationsofourstudy Ž‹‡ƒ‹‹Žetal.ƒ†‘‘’atal.,™‡†‹†‘–‹˜‡•–‹‰ƒ–‡ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‘” CYP11B2 ‡š’”‡••‹‘ —†‡” ‡Ž‡˜ƒ–‡† ‡š–”ƒ ‡ŽŽ—Žƒ” Ϊ ‹ ‘—” •–—†› ‘ CACNA1H S1073Cͳͳͷǡ͵ʹ͹Ǥ‘•‹†‡”‹‰‘—”‹˜‡•–‹‰ƒ–‹‘•‘ˆCACNA1HM1549Vǡ ‘†— –‡†•‹‹Žƒ”Ž› –‘–Š‡‘‡•‘ˆCACNA1HS1073Cǡ‹–‹•—Ž‹‡Ž›–Šƒ–‘—”‡š’‡”‹‡–ƒŽ•‡–—’™‘—Ž† ‘Ǧ ‡ƒŽƒ‡ˆˆ‡ –‘ˆ–Š‡—–ƒ–‹‘—†‡”„ƒ•ƒŽ ‘†‹–‹‘•–Šƒ–™‘—Ž†„‡ ‘‡‡˜‹†‡–ƒˆ–‡” •–‹—Žƒ–‹‘Ǥ  ‘–”ƒ•–ǡ†‹ˆˆ‡”‡ ‡•„‡–™‡‡™‹Ž†–›’‡ƒ†ͳͷͶͻ„‡ ƒ‡Ž‡••’”‘Ǧ ‘— ‡†ƒˆ–‡”•–‹—Žƒ–‹‘—†‡”‘—”‡š’‡”‹‡–ƒŽ ‘†‹–‹‘•͵Ͷ͸ȋ ‘’ƒ”‡•‡ –‹‘

͹͵ ϴŝƐĐƵƐƐŝŽŶ



&ŝŐƵƌĞϵ͘,ŽŵŽůŽŐƵĞƐŽĨƚŚĞƉƌŽƚĞŝŶƌĞŐŝŽŶƐĐŽŶƚĂŝŶŝŶŐŚƵŵĂŶEϭ,^ϭϬϳϯ͕ZDϱϲϱϲĂŶĚ,ϭ ^ϭϱϰͺ^ϭϱϱ͘ͿKƌƚŚŽůŽŐƵĞƐŽĨƚŚĞEϭ,^ϭϬϳϯͲĐŽŶƚĂŝŶŝŶŐƉƌŽƚĞŝŶƌĞŐŝŽŶĂĐƌŽƐƐĚŝĨĨĞƌĞŶƚƐƉĞĐŝĞƐ͘^ϭϬϳϯ ŝƐĐŽŶƐĞƌǀĞĚŝŶƉƌŝŵĂƚĞƐ͕ďƵƚŶŽƚŝŶŽƚŚĞƌŵĂŵŵĂůŝĂŶƐƉĞĐŝĞƐ͘ͿWĂƌĂůŽŐƵĞƐŽĨƚŚĞEϭ,^ϭϬϳϯͲĐŽŶͲ ƚĂŝŶŝŶŐƉƌŽƚĞŝŶƌĞŐŝŽŶĂĐƌŽƐƐƚŚĞĚŝĨĨĞƌĞŶƚŚƵŵĂŶǀŽůƚĂŐĞͲŐĂƚĞĚĐĂůĐŝƵŵĐŚĂŶŶĞůɲϭƐƵďƵŶŝƚƐ͘dŚĞ^ϭϬϳϯƌĞƐͲ ŝĚƵĞŝƐŶŽƚĐŽŶƐĞƌǀĞĚ͘ͿKƌƚŚŽůŽŐƵĞƐŽĨƚŚĞZDϱϲϱϲͲĐŽŶƚĂŝŶŝŶŐƌĞŐŝŽŶ͘dŚĞƌĞƐŝĚƵĞŝƐĐŽŶƐĞƌǀĞĚĂĐƌŽƐƐ ĚŝĨĨĞƌĞŶƚŵĂŵŵĂůŝĂŶƐƉĞĐŝĞƐ͘ͿKƌƚŚŽůŽŐƵĞƐŽĨƚŚĞ,ϭ^ϭϱϰͺ^ϭϱϱͲĐŽŶƚĂŝŶŝŶŐƌĞŐŝŽŶ͘/ŶŵĂŵŵĂůƐ͕ƚŚŝƐ ƌĞŐŝŽŶĐŽŶƚĂŝŶƐŵƵůƚŝƉůĞĐŽŶƐĞĐƵƚŝǀĞƐĞƌŝŶĞƌĞƐŝĚƵĞƐ͕ďƵƚƚŚĞŝƌŶƵŵďĞƌǀĂƌŝĞƐ͘ůŝŐŶŵĞŶƚƐǁĞƌĞĚŽŶĞǀŝĂƚŚĞ ƵŶŝƉƌŽƚ ǁĞďƐŝƚĞ ;ŚƚƚƉ͗ͬͬǁǁǁ͘ƵŶŝƉƌŽƚ͘ŽƌŐͬͿ͘ hŶŝƉƌŽƚ ƌĞĨĞƌĞŶĐĞƐ ƵƐĞĚ͗ KϵϱϭϴϬ͕ ,ϮYϵ͕ 'ϯZ^ϲ͕ &ϳϵ͕ YϵYϲϬ͕KϴϴϰϮϳ͕&ϲsDϭ͕&ϲhϬ,ϯ͕'ϭEϭϲϬ͕Kϰϯϰϵϳ͕YϵWϬyϰ͕YϬϭϲϲϴ͕Yϭϯϵϯϲ͕Yϭϯϲϵϴ͕KϲϬϴϰϬ͕KϬϬϱϱϱ͕ YϬϬϵϳϱ͕Yϭϱϴϳϴ͕YϵϲϭϮ͕<ϳWϭ͕'ϯYt>ϭ͕&ϲdϳϰ͕YϱWYWϵ͕YϱWϯ͕&ϲyz,Ϭ͕&ϭY/hϲ͕Yϵh/ϯϲ͕&ϲy^ϭ͕ YϵYzϮ͕'ϭ^'tϳ͕YϬWE&ϳ 

ͺǤ͵ǤͳȌǤ —”–Š‡”‘”‡ǡ—•–‹—Žƒ–‡† ‘†‹–‹‘•”‡’”‡•‡––Š‡•‹–—ƒ–‹‘‹ ’ƒ–‹‡–• ‘•–ƒ —”ƒ–‡Ž›ǡ™Š‡”‡–Š‡‹••—’’”‡••‡†ƒ†‡š–”ƒ ‡ŽŽ—Žƒ”Ϊ‹•‹‘”„‡Ž‘™–Š‡ ‘”ƒŽ’Š›•‹‘Ž‘‰‹ ƒŽ”ƒ‰‡Ǥ‡˜‡”–Š‡Ž‡••ǡ‹–‹•’‘••‹„Ž‡–Šƒ–•ƒŽŽ‡ˆˆ‡ –•‘ƒŽ†‘•–‡Ǧ ”‘‡’”‘†— –‹‘‘”‡ˆˆ‡ –•„ƒ•‡†‘ƒ†‹ˆˆ‡”‡–—†‡”Ž›‹‰ Šƒ‰‡‹ Šƒ‡Ž’”‘’‡”Ǧ –‹‡•‹‰Š–‘–„‡‹†‡–‹ˆ‹‡†—†‡”‘—”‡š’‡”‹‡–ƒŽ ‘†‹–‹‘•ǤInvivoǡ–Š‡›‹‰Š–•–‹ŽŽ ‘–”‹„—–‡–‘ƒ ’Š‡‘–›’‡ǡ‡•’‡ ‹ƒŽŽ›‹ ‘Œ— –‹‘™‹–Š‘–Š‡”‰‡‡–‹ ‘”‡˜‹Ǧ ”‘‡–ƒŽˆƒ –‘”•Ǥ

‘”•‘‡ͳ —–ƒ–‹‘•ȋͳͻ͸ǡʹͲͺ͵ƒ†ͳͻͷͳȌˆ‘—†‹ ’ƒ–‹‡–•ǡ ƒ‹‹Žetal.†‡• ”‹„‡†‘ƒ”‡†‡ˆˆ‡ –•‘ Šƒ‡Žƒ –‹˜ƒ–‹‘‘”‹ƒ –‹˜ƒ–‹‘ǡ„—–”‡Ǧ ’‘”–‡†•‹‰‹ˆ‹ ƒ–†‹ˆˆ‡”‡ ‡•‹ Šƒ‡Žˆƒ ‹Ž‹–ƒ–‹‘ͳͳͷǤ  ”‡ƒ•‡† Šƒ‡Žˆƒ ‹Ž‹–ƒ–‹‘ ™‘—Ž†ƒŽŽ‘™ˆ‘”‹ ”‡ƒ•‡†ƒʹΪ‹ˆŽ—š‹–‘–Š‡ ‡ŽŽ—’‘—Ž–‹’Ž‡ ‘•‡ —–‹˜‡†‡’‘Žƒ”Ǧ ‹œ‹‰’—Ž•‡•Ǥ‡‹–Š‡” Šƒ‡Žˆƒ ‹Ž‹–ƒ–‹‘‘”‡ƒ•—”‡‡–•‘ˆ‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪ ‘Ǧ

͹Ͷ ϴŝƐĐƵƐƐŝŽŶ ‡–”ƒ–‹‘•™‡”‡•—„Œ‡ –‘ˆ‘—”‹˜‡•–‹‰ƒ–‹‘ǤŠ‡”‡ˆ‘”‡ǡ‡ˆˆ‡ –•‘ˆ–Š‡ͳͲ͹͵—–ƒǦ –‹‘‘‘–Š‡” Šƒ‡Ž’”‘’‡”–‹‡•„—–ƒ –‹˜ƒ–‹‘ƒ†‹ƒ –‹˜ƒ–‹‘ ƒ‘–„‡‡š Ž—†‡†Ǥ Š‡›‹‰Š–‹ˆŽ—‡ ‡‹–”ƒ ‡ŽŽ—Žƒ”ƒʹΪŽ‡˜‡Ž•™‹–Š‘—–ƒ”‡†‡ˆˆ‡ –•‘ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘ƒ–„ƒ•ƒŽŽ‡˜‡ŽǤ

8.3.2.3 Outlook:InvestigationsofmutationsinARMC5andDACH1 ‹ ‡‘—”‹˜‡•–‹‰ƒ–‹‘•†‹†‘–’”‘˜‹†‡ƒ›‡˜‹†‡ ‡–Šƒ––Š‡CACNA1HS1073C—–ƒǦ –‹‘‹‰Š– ƒ—•‡ ǡ‘–Š‡”‰‡”Ž‹‡—–ƒ–‹‘•ˆ‘—†‹‰‡‡•‹’Ž‹ ƒ–‡†‹ƒŽ†‘•–‡Ǧ ”‘‡Š‘‡‘•–ƒ•‹•‘” •Š‘—Ž†„‡‹˜‡•–‹‰ƒ–‡†Ǥ ͳŠƒ•„‡‡•—‰‰‡•–‡†–‘„‡ƒ ‡‰ƒ–‹˜‡”‡‰—Žƒ–‘”‘ˆCYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘ͺ͸ǤŠ‡”‡ˆ‘”‡ǡƒ Ž‘••Ǧ‘ˆǦˆ— –‹‘—–ƒ–‹‘™‘—Ž†„‡‡š’‡ –‡†–‘‹ ”‡ƒ•‡ƒŽ†‘•–‡”‘‡’”‘†— –‹‘Ǥ†—Ǧ ’Ž‹ ƒ–‹‘ ‘ˆ •‡”‹‡ ”‡•‹†—‡• ȋDach1 S154_S155dupȌ ™ƒ• ˆ‘—† ‹ ˆ‘—” ‘ˆ ˆ‹˜‡ ˆƒ‹Ž› ‡„‡”•ǤͳͷͶ̴ͳͷͷƒ”‡Ž‘ ƒ–‡†‹ƒ•‡“—‡ ‡‘ˆ—Ž–‹’Ž‡ ‘•‡ —–‹˜‡•‡”‹‡”‡•‹†—‡•Ǥ  ‘’ƒ”‹•‘‘ˆ‘”–Š‘Ž‘‰—‡•”‡˜‡ƒŽ•–Šƒ––Š‡‹”—„‡”ƒ’’‡ƒ”•‘––‘„‡ ‘•‡”˜‡† ƒ ”‘•••’‡ ‹‡•ȋ ‘’ƒ”‡ ‹‰—”‡ͻȌǤŠ‹•‹†‹ ƒ–‡•–Šƒ––Š‡‡šƒ –—„‡”‘ˆ•‡”‹‡ ”‡•‹†—‡•‹–Š‹•”‡‰‹‘‹‰Š–‘–Šƒ˜‡ƒ˜‹–ƒŽ‡ˆˆ‡ –‘’”‘–‡‹ˆ— –‹‘ƒ†–Šƒ––Š‡ ‡ˆˆ‡ –‘ˆƒ•‡”‹‡†—’Ž‹ ƒ–‹‘ƒ––Š‹•’‘•‹–‹‘‹‰Š–„‡‹‘”Ǥ‘–Š‡”ˆƒ –•—’’‘”–‹‰ –Š‹•‹†‡ƒ‹•–Šƒ––Š‡”‡‰‹‘•—””‘—†‹‰DACH1S154_S154‹•”‹ Š‹•ǡ™Š‹ Šƒˆˆ‡ – –Š‡—„‡”‘ˆ ‘•‡ —–‹˜‡•‡”‹‡•‹–Š‹•”‡‰‹‘ƒ†–Š‡”‡ˆ‘”‡”‡†‡”ƒ Ž‹‹ ƒŽ”‡Ž‡Ǧ ˜ƒ ‡”ƒ–Š‡”—Ž‹‡Ž›ȋƒ„Ž‡ͶȌǤˆ‘–‡ǡ†ƒ–ƒ„ƒ•‡”‡’‘”–•‘–Š‡ˆ”‡“—‡ ›‘ˆ ͳ ͳͷͶ̴ͳͷͷ†—’˜ƒ”›ȋͲǤͳʹ͸ͳȉͳͲǦ͵‹–Š‡šƒ–ƒ„ƒ•‡ƒ†ͲǤͻ͸ʹ͹͵ƒ ‘”†‹‰–‘–Š‡ ‰‡‘‡„”‘™•‡”ǡ ‘’ƒ”‡•‡ –‹‘͹ǤͶǤ͵ȌǤ  ƒ•‡‘ˆƒƒ –—ƒŽƒŽŽ‡Ž‡ˆ”‡“—‡ ›‘ˆ ̱ͲǤͻ͸ǡƒ†‹•‡ƒ•‡ ƒ—•‹‰‡ˆˆ‡ –‘ˆ–Š‡˜ƒ”‹ƒ–™‘—Ž†„‡‹’”‘„ƒ„Ž‡Ǥ

‘–Š‡” —–ƒ–‹‘ ˆ‘—† ‹ ˆ‹˜‡ ‘—– ‘ˆ ˆ‹˜‡ ‡š‘‡Ǧ•‡“—‡ ‡† ˆƒ‹Ž›‡„‡”•™ƒ• ARMC5A656S.Š‹•”‡•‹†—‡ǡƒ•™‡ŽŽƒ•–Š‡•—””‘—†‹‰”‡•‹†—‡•ǡƒ”‡ ‘•‡”˜‡†‹ƒǦ ƒŽ•ǡ„—– ƒ†‹ˆˆ‡”ƒ”‡†Ž›‹‘–Š‡”˜‡”–‡„”ƒ–‡•ȋ ‘’ƒ”‡ ‹‰—”‡ͻȌǤŠ‹• ‘’Ž‹Ǧ ƒ–‡•‡˜ƒŽ—ƒ–‹‘‘ˆ–Š‡”‡‰‹‘ǯ•”‘Ž‡‹’”‘–‡‹ˆ— –‹‘Ǥ –Š‡˜‹ ‹‹–›‘ˆ͸ͷ͸ǡƒ͸Ͷ͵ —–ƒ–‹‘Šƒ•’”‡˜‹‘—•Ž›„‡‡†‡• ”‹„‡†‹’ƒ–‹‡–•™‹–Š ǤŠ‡—–ƒ–‹‘™ƒ•’”‡Ǧ †‹ –‡†–‘„‡†‡–”‹‡–ƒŽ–‘’”‘–‡‹ˆ— –‹‘͵ʹͻǤ‘—–ƒ–‹‘•‹–Š‡†‹”‡ –˜‹ ‹‹–›‘ˆ ͸ͷ͸ ™‡”‡ †‹• ‘˜‡”‡† ‹ ƒ ”‘‘†—Žƒ” ƒ†”‡ƒŽ Š›’‡”’Žƒ•‹ƒǡ „—– •‘‡ ƒ”‡ Ž‘ ƒ–‡† ”‘—‰ŠŽ›‹–Š‡•ƒ‡”‡‰‹‘‘ˆ–Š‡’”‘–‡‹ȋͳͷͲƒ‹‘ƒ ‹†•—’•–”‡ƒ‘”†‘™•–”‡ƒ ‘ˆ͸ͷ͸ǡƒ‡Ž›ͷͶͺǡͷͻ͵ǡ͸ͳͻǡ͹Ͳʹ̴͹Ͳ͸†‡ŽȌ͵ʹͺǡ͵ͺͶǡ͵ͺͷǤ

‘‡˜ƒŽ—ƒ–‡–Š‡”‘Ž‡‘ˆARMC5A656Sƒ†DACH1S154_S155dupƒ•ƒ’—–ƒ–‹˜‡ ƒ—•‡‘ˆ ǡinvitro‹˜‡•–‹‰ƒ–‹‘••‹‹Žƒ”–‘–Š‘•‡’‡”ˆ‘”‡†ˆ‘”CACNA1HS1073C‘”M1549V

͹ͷ ϴŝƐĐƵƐƐŝŽŶ •Š‘—Ž†„‡ ‘†— –‡†Ǥ ‹˜‡–Š‡ƒˆ‘”‡‡–‹‘‡†‹ˆ‘”ƒ–‹‘ǡARMC5A656S ‘—Ž†„‡ ‘•‹†‡”‡†ƒ•–”‘‰‡” ƒ†‹†ƒ–‡–ŠƒDACH1S154_S155dup,•‘–Š‡ˆ‘”‡”—–ƒ–‹‘ ‹‰Š–”‡’”‡•‡–ƒ•—‹–ƒ„Ž‡•–ƒ”–‹‰’‘‹–ˆ‘”ˆ—”–Š‡”‡š’‡”‹‡–•Ǥˆ‘–‡ǡ ƒ””‹‡”•‘ˆ ‘–Š‡”˜‘Ž–ƒ‰‡Ǧ‰ƒ–‡† ƒŽ ‹— Šƒ‡Ž—–ƒ–‹‘•‹’Ž‹ ƒ–‡†‹ †‘‘–ƒŽ™ƒ›•†‹•’Žƒ› ƒ ’Š‡‘–›’‡ͳͳͺǡͳʹͳǡ͵ʹͲǤŠ‹Ž‡‡˜‹”‘‡–ƒŽˆƒ –‘”•ƒˆˆ‡ –‹‰’‡‡–”ƒ ‡ƒ”‡†‹ˆˆ‹Ǧ —Ž––‘•‹—Žƒ–‡‹ ‡ŽŽ —Ž–—”‡‡š’‡”‹‡–•ǡ ‘Ǧ–”ƒ•ˆ‡ –‹‘‘ˆ–™‘‘”ƒŽŽ–Š”‡‡‘ˆ–Š‡ †‹• ‘˜‡”‡†—–ƒ–‹‘•‹‰Š–‹‹ –Š‡’ƒ–‹‡–•ǯ‰‡‡–‹ ’”‡†‹•’‘•‹–‹‘•‘”‡ Ž‘•‡Ž›ǡ ƒ†”‡˜‡ƒŽ ——Žƒ–‹˜‡‡ˆˆ‡ –•‘ˆ–Š‡˜ƒ”‹ƒ–•‘ƒŽ†‘•–‡”‘‡’”‘†— –‹‘–Šƒ–‹‰Š–‘– „‡†‡–‡ –‡†‹ƒƒƒŽ›•‹•‘ˆ–Š‡‹†‹˜‹†—ƒŽ—–ƒ–‹‘•Ǥ

‡•’‹–‡‘—”‹˜‡•–‹‰ƒ–‹‘•‘ˆ–Š‡CACNA1HS1073C—–ƒ–‹‘ǡ–Š‡‘”‹‰‹‘ˆ ‹–Š‡ ’ƒ–‹‡–•‹–™ƒ•†‹• ‘˜‡”‡†‹”‡ƒ‹•— Ž‡ƒ”Ǥ —”–Š‡”•–—†‹‡•‘ˆƒ††‹–‹‘ƒŽŽ›‹†‡–‹ˆ‹‡† —–ƒ–‹‘•‹DACH1ƒ†ARMC5‹‰Š–’”‘˜‹†‡ˆ—”–Š‡”‹•‹‰Š–‹–‘–Š‡—†‡”Ž›‹‰‰‡Ǧ ‡–‹  ƒ—•‡•Ǥ

 dĂďůĞ ϰ͘ <ŶŽǁŶ ǀĂƌŝĂŶƚƐ ŝŶ,ϭ ĂůƚĞƌŝŶŐ ƚŚĞ ŶƵŵďĞƌ ŽĨ ĐŽŶƐĞĐƵƚŝǀĞ ƐĞƌŝŶĞ ƌĞƐŝĚƵĞƐ ƐƵƌƌŽƵŶĚŝŶŐ ^ϭϱϰͺ^ϭϱϱ͘ĂƐĞĚŽŶŝŶĨŽƌŵĂƚŝŽŶĨƌŽŵƚŚĞdžĂƚĂďĂƐĞ͘'ĞŶŽŵŝĐƉŽƐŝƚŝŽŶŝŶŚƵŵĂŶŐĞŶŽŵĞďƵŝůĚϭϵ͘ ĨĨĞĐƚƐŽŶƚŚĞ,ϭƉƌŽƚĞŝŶďĂƐĞĚŽŶƚŚĞŐĞŶŽŵŝĐƉŽƐŝƚŝŽŶƵƐŝŶŐƚŚĞh^ŐĞŶŽŵĞďƌŽǁƐĞƌ͘ΎDĂƌŬƐƚŚĞ ,ϭ^ϭϱϰͺ^ϭϱϱĚƵƉŵƵƚĂƚŝŽŶĨŽƵŶĚŝŶƚŚĞƉĂƚŝĞŶƚƐĚŝƐĐƵƐƐĞĚŝŶƚŚŝƐǁŽƌŬ͘

Chromo Effecton Allele some Position Basechange protein Annotation frequency ‹ˆ”ƒ‡†‡Ǧ ͳ͵ ͹ʹͶͶͲͶͶ͵  ε ͳͷͷ†‡Ž ͲǤͲͲ͸ͷͳͺ Ž‡–‹‘

‹ˆ”ƒ‡†‡Ǧ ͳ͵ ͹ʹͶͶͲͶͶ͵    ε ͳͷ͵̴ͳͷͷ†‡Ž ͲǤͲͲͲͳʹ͸ͳ Ž‡–‹‘

‹ˆ”ƒ‡‹Ǧ ͳ͵ ͹ʹͶͶͲͶͶ͵ ε  ͳͷͷ†—’ ͲǤͲͲͲͷͲͶ͸ •‡”–‹‘ ‹ˆ”ƒ‡‹Ǧ ͳ͵ ͹ʹͶͶͲͶͶ͵ ε   ͳͷͶ̴ͳͷͷ†—’ȗ ͲǤͲͲͲͳʹ͸ͳ •‡”–‹‘ ‹ˆ”ƒ‡†‡Ǧ ͳ͵ ͹ʹͶͶͲͶ͸͹  ε ͳͶ͹†‡Ž ͲǤͲͳ͸Ͳ͵ Ž‡–‹‘ ‹ˆ”ƒ‡‹Ǧ ͳ͵ ͹ʹͶͶͲͶ͸͹ ε  ͳͶ͹†—’ ͲǤͲͲͲʹ͵ʹͶ •‡”–‹‘ ‹ˆ”ƒ‡‹Ǧ ͳ͵ ͹ʹͶͶͲͶ͸͹ ε   ͳͶ͸̴ͳͶ͹†—’ ͲǤͲͲͲͲ͹͹Ͷ͸ •‡”–‹‘  

͹͸ ϵZĞĨĞƌĞŶĐĞƐ  9 References

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ͻ͵ ϵZĞĨĞƌĞŶĐĞƐ  ͵ͺͳǤ ”ƒ†‡„—”‰‡”ǡǤetal.‘••‹„Ž‡‘Ž‡ ˆ‘”‹–‘ Š‘†”‹ƒŽƒŽ ‹—‹ ‰‹‘–‡•‹ Ǧƒ†‘–ƒ••‹—Ǧ –‹—Žƒ–‡†–‡”‘‹†‘‰‡‡•‹•‹‘˜‹‡ †”‡ƒŽ Ž‘‡”—Ž‘•ƒ‡ŽŽ•Ǥ Endocrinology137,ͷͷͶͶȂͷͷͷͳȋͳͻͻ͸ȌǤ ͵ͺʹǤ ˆ–‹ ƒǡǤǤƬƒ’‘‹ǡ ǤǤ ‡‰—Žƒ–‹‘‘ˆ‡—”‘ƒŽǦ–›’‡ ƒŽ ‹— Šƒ‡Ž•ǤTrendsPharmacol.Sci.30, ͵ʹȂͶͲȋʹͲͲͻȌǤ ͵ͺ͵Ǥ ‡”‘ǡǤǤetal.š–‡†‡†•’‡ –”—‘ˆ ‹†‹‘’ƒ–Š‹ ‰‡‡”ƒŽ‹œ‡†‡’‹Ž‡’•‹‡• ƒ••‘ ‹ƒ–‡†™‹–ŠCACNA1Hˆ— –‹‘ƒŽ ˜ƒ”‹ƒ–•ǤAnn.Neurol.62,ͷ͸ͲȂͷ͸ͺ ȋʹͲͲ͹ȌǤ ͵ͺͶǤ ƒ— œǡ ǤǤetal.ƒ ”‘‘†—Žƒ”†”‡ƒŽ ›’‡”’Žƒ•‹ƒ†—‡–‘—–ƒ–‹‘•‹ƒ ”ƒ†‹ŽŽ‘‡’‡ƒ–‘–ƒ‹‹‰ͷ ȋARMC5Ȍ ‡‡ǣŽ‹‹ ƒŽƒ† ‡‡–‹  ˜‡•–‹‰ƒ–‹‘ǤJ.Clin.Endocrinol.Metab. 99,ͳͳͳ͵ȂͳͳͳͻȋʹͲͳͶȌǤ ͵ͺͷǤ ƒ‰Ž‹ƒ”†‹ǡǤetal.ARMC5—–ƒ–‹‘•”‡ ‘‘‹ ƒ‹Ž‹ƒŽ‹Žƒ–‡”ƒŽ ƒ ”‘‘†—Žƒ”†”‡ƒŽ ›’‡”’Žƒ•‹ƒǤJ. Clin.Endocrinol.Metab.99,ͳ͹ͺͶȂ ͳ͹ͻʹȋʹͲͳͶȌǤ

ͻͶ ϭϬĂŶŬƐĂŐƵŶŐ

10 Danksagung Š†ƒ‡‹˜ǤǦ”‘ˆǤ”Ǥ‡†Ǥ–‡ Š‘ŽŽˆò”†‹‡ډŽ‹ Š‡‹–‹‹Š”‡””„‡‹–•‰”—’’‡‹†‡”šǦ ’‡”‹‡–‡ŽŽ‡‡’Š”‘Ž‘‰‹‡—† ›’‡”–‡•‹‘Ž‘‰‹‡œ—’”‘‘˜‹‡”‡Ǥ‡‹ƒ‰‹Ž–ƒ†‹‡•‡” –‡ŽŽ‡ƒ— Š‹˜ǤǦ”‘ˆǤ”Ǥ‡†Ǥƒ”•Š”‹•–‹ƒ—’‹•‡‹‡”–‡ŽŽ—‰ƒŽ•‡‹–‡”†‡”Ž‹‹ˆò” ‡’Š”‘Ž‘‰‹‡†‡•‹˜‡”•‹–¡–•Ž‹‹—•ò••‡Ž†‘”ˆȋȌǤ

‡‹–‡”Š‹„‡†ƒ‡‹ Š‹ Š„‡‹‹˜ǤǦ”‘ˆǤ”Ǥ‡†Ǥ–‡ Š‘ŽŽˆò”†‹‡ډŽ‹ Š‡‹–‡—††‹‡ –‡”•–ò–œ—‰ǡ†‹‡‹”‹ƒŠ‡†‡”‡ƒ”„‡‹–—‰†‡”Š‹‡”ƒ—ˆ‰‡ˆòŠ”–‡”‘Œ‡–‡‰‡„‘–‡ ™—”†‡ǡ•‘™‹‡ˆò”†‹‡‘””‡–—”‡—†"†‡”—‰•˜‘”• ŠŽ¡‰‡œ—†‹‡•‡”‹••‡”–ƒ–‹‘•• Š”‹ˆ–Ǥ

—釔†‡†ƒ‡‹ Š‹˜ǤǦ”‘ˆǤ”Ǥ‡†ǤŠ”‹•–‘’Š ƒŠŽ‡†ƒˆò”ǡ†ƒ••‡”‡‹”‘‘–‹‘•˜‘”Ǧ Šƒ„‡ƒŽ•™‡‹–„‡–”‡—‡”„‡‰Ž‡‹–‡–Šƒ–—†•‹ Š†‹‡‡‹–‰‡‘‡Šƒ–ǡ†‡ ‘”–• Š”‹––†‡””‘Ǧ Œ‡–‡œ—˜‡”ˆ‘Ž‰‡Ǥ

Š†ƒ‡”Ǥ‡†Ǥ˜‡–Ǥ —Ž‹ƒ Š‡™‡ǡ‹’ŽǤǦŠ‡Ǥ”‹ ‡‹†‡Žǡ”Ǥ”‡”Ǥƒ–Ǥ‡Š‹‡Ž—†”Ǥ ”‡”Ǥƒ–Ǥ —†”—ƒŽ‡†ƒ•‘™‹‡ƒŽŽ‡ƒ†‡”‡ƒ–—‡ŽŽ‡—†‡Š‡ƒŽ‹‰‡‹–‰Ž‹‡†‡”†‡”   Š‘ŽŽˆò”‹Š”‡–‡”•–ò–œ—‰ǡ‹•„‡•‘†‡”‡ˆò”†‡’‘•‹–‹˜‡™‹••‡• Šƒˆ–Ž‹ Š‡—•–ƒ—• Š —††‹‡‰—–‡—•ƒ‡ƒ”„‡‹–ƒ‰‡‡‹•ƒ‡”‘Œ‡–‡Ǥ— ŠƒŽŽ‡™‡‹–‡”‡‹–‰Ž‹‡†‡”†‡” š’‡”‹‡–‡ŽŽ‡‡’Š”‘Ž‘‰‹‡—† ›’‡”–‡•‹‘Ž‘‰‹‡Ú Š–‡‹ Šˆò”‹Š”‡˜‹‡Žˆ¡Ž–‹‰‡–‡”•–ò–Ǧ œ—‰—††‹‡‰—–‡—•ƒ‡ƒ”„‡‹–†ƒ‡Ǥ‡•‘†‡”‡”ƒ‰‹Ž–†ƒ„‡‹†‡–‡ Š‹• Š‡•Ǧ •‹•–‡–‹‡Žƒƒ—˜‹Œƒǡ‹ ‘Žƒ—Š”—†Š”‹•–‹ƒ Š™ƒ†–ˆò” Š”‡ ‹Žˆ‡ǡ˜‘”ƒŽŽ‡‹ ‰ƒ‰‹–ƒ†‹‹•–”ƒ–‹˜‡ Š™‹‡”‹‰‡‹–‡Ǥƒ”ò„‡”Š‹ƒ—•†ƒ‡‹ Š‹˜ǤǦ”‘ˆǤ”Ǥ‡†Ǥ ‡Ž‹š‡—• ŠŽ‡‹ǡ”Ǥƒ”ƒŠƒ›‡ȋ„‡‹†‡Ž‹‹—†‡”‹˜‡”•‹–¡–ò Š‡Ȍ—†”Ǥ‡†Ǥ ƒ„”‹‡Ž–ÚŽ–‹‰ȋ ‘”• Š—‰•œ‡–”— òŽ‹ ŠȌˆò”†‹‡”„‡‹–ƒ‰‡‡‹•ƒ‡”‘Œ‡–‡Ǥ‡‹–‡”Ǧ Š‹Ú Š–‡‹ Š‹˜ǤǦ”‘ˆǤ”Ǥ‡†Ǥƒ‹‡” ƒƒ•ǡ”Ǥ”‡”Ǥƒ–Ǥ‘Ǧƒ–”‹ ƒ†‡††——†”Ǥ”‡”Ǥ ƒ–Ǥ–‡ˆƒ‹‡ ‡›Šƒ—•†‡”Ž‹‹ˆò” ¡ƒ–‘Ž‘‰‹‡ǡ‘Ž‘‰‹‡—†Ž‹‹• Š‡ —‘Ž‘‰‹‡†‡• †ƒˆò”†ƒ‡ǡ†ƒ•••‹‡—•‡”‡””„‡‹–•‰”—’’‡‹Š”ƒšƒ ‡”¡–•‘‰”‘éœò‰‹‰œ—”‡”ˆòǦ ‰—‰‰‡•–‡ŽŽ–Šƒ„‡—††ƒ„‡‹‹‡”•‡Š”Š‹Žˆ•„‡”‡‹–™ƒ”‡Ǥ

Š†ƒ‡ƒ‹‡Ž ƒ†‡ŽǡǤ Ǥǡ”Ǥ”‡”Ǥƒ–Ǥ ”ƒ ƒ•„‡†‡”ǡ”Ǥ‡†Ǥ˜‡–Ǥ —Ž‹ƒ Š‡™‡—† ‹’ŽǤǦŠ‡Ǥ”‹ ‡‹†‡Žˆò”†ƒ•‘””‡–—”Ž‡•‡†‹‡•‡””„‡‹–Ǥ—”‡"†‡”—‰•˜‘”• ŠŽ¡‰‡—† ’—Ž•‡Šƒ„‡‹”•‡Š”‰‡Š‘Žˆ‡Ǥ

‡‹‡” ƒ‹Ž‹‡—†‡‹‡ ”‡—†‡Ú Š–‡‹ Š†ƒ‡ǡ†ƒ•••‹‡‹”‹†‡”˜‘ ڊ‡—† ‹‡ˆ‡‰‡’”¡‰–‡”‘‘–‹‘•œ‡‹–œ—”‡‹–‡‰‡•–ƒ†‡Šƒ„‡Ǥ‡•‘†‡”‡”ƒ‰‹Ž–†ƒ„‡‹‡‹Ǧ ‡Ž–‡” ڔ‰—†”•—Žƒ‡‹‡”Ǥ



ͻͷ ϭϭƉƉĞŶĚŝdž 11 Appendix

11.1Projectsfeaturedinthisworkandcontributions

11.1.1Project1(Section7.1) Ǥ Ǥ Š‘ŽŽǡ ǤǤ ‡ƒŽ›ǡǤŠ‹‡ŽǡǤǤ ‘•‡ ƒǡǤǤ”‘™ǡ ǤǤ—•–ƒǡǤ Ǥ ‘”‡ǡ Ǥ‹‡–”‹ Šǡ Ǥ‹‡‡”ǡǤò òÚ›ŽòǡǤǤ‡‹‡”ǡǤǤ‡‹•ǡ Ǥ ‘Šǡ Ǥ”‹•–‹ƒ•‡ǡǤ ƒŠƒŒƒǡǤ‘”ƒŠǡǤǤ‹ˆ–‘ǡǤǤ”ƒ•ƒ†ǡƒ†Ǥƒ”Ž‹‰ǡDz‘˜‡Ž•‘ƒ–‹ —–ƒ–‹‘• ‹’”‹ƒ”›Š›’‡”ƒŽ†‘•–‡”‘‹•ƒ”‡”‡Žƒ–‡†–‘–Š‡ Ž‹‹ ƒŽǡ”ƒ†‹‘Ž‘‰‹ ƒŽƒ†’ƒ–Š‘Ž‘‰‹ ƒŽ ’Š‡‘–›’‡ǡdzŽ‹‹ ƒŽ†‘ ”‹‘Ž‘‰›ǡ˜‘ŽǤͺ͵ǡ’’Ǥ͹͹ͻȂ͹ͺͻǡʹͲͳͷǤ

•–Š‡”‡‹‡”ǯ• ‘–”‹„—–‹‘–‘–Š‡’—„Ž‹ ƒ–‹‘ǣ̱ͷΨȋ ˆ”‘–‹••—‡ǡ ƒƒŽ›•‹•ƒ† ‘ˆ‹”ƒ–‹‘‘ˆKCNJ5—–ƒ–‹‘•ˆ‘”ͺ‘ˆ͸ʹ‡™Ž›ƒƒŽ›œ‡†’ƒ–‹‡–•ǡ‹‹Ǧ –‹ƒŽ•–‘• ”‡‡ˆ‘”CACNA1DǡATP1A1ǡATP2B3ƒ†CTNNB1—–ƒ–‹‘•ˆ‘”ͺ‘ˆ͸ʹ ‡™Ž›ƒƒŽ›œ‡†’ƒ–‹‡–•™‹–Š‹‘”Š‡Ž’„›‡Š‹‡ŽǡCACNA1DǡATP1A1ǡATP2B3 ƒ†CTNNB1 ‘ˆ‹”ƒ–‘”›•ƒ†—–ƒ–‹‘ƒƒŽ›•‹•ˆ‘”–Š‡•‡ͺ’ƒ–‹‡–•’‡”ˆ‘”‡† „›‡Š‹‡ŽȌ

11.1.2Project2(Section7.2) Ǥ Ǥ Š‘ŽŽǡǤ„”‹‘ŽƒǡǤŠƒ‰ǡǤǤ‡‹‡”ǡǤŽ—‡”ǡǤ Ǥƒœ‹‡” œƒǡ ǤŠƒ‰ǡ Ǥ ‘›‡”ǡ ǤǤ‡”‡ŽǡǤƒ‰ǡƒ†ǤǤ‹ˆ–‘ǡDzƒ ”‘Ž‹†‡••‡Ž‡ –‹˜‡Ž›‹Š‹„‹–—–ƒ–  ͷ’‘–ƒ••‹— Šƒ‡Ž•–Šƒ– ƒ—•‡ ƒŽ†‘•–‡”‘‡Ǧ’”‘†— ‹‰ ƒ†‡‘ƒǡdz ‘—”ƒŽ‘ˆ Ž‹‹ ƒŽ ˜‡•–‹‰ƒ–‹‘ǡ˜‘ŽǤͳʹ͹ǡ‘Ǥ͹ǡ’’ǤͳȂͳʹǡʹͲͳ͹Ǥ

•–Š‡”‡‹‡”ǯ• ‘–”‹„—–‹‘–‘–Š‡’—„Ž‹ ƒ–‹‘ǣ̱ͳͷΨȋ’‡”ˆ‘”ƒ ‡ƒ††ƒ–ƒƒƒŽ›•‹• ‘ˆ‡š’‡”‹‡–•–‘–‡•––Š‡‡ˆˆ‡ –•‘ˆ”‘š‹–Š”‘› ‹‘CYP11B2‡š’”‡••‹‘ƒ†ƒŽ†‘•Ǧ –‡”‘‡’”‘†— –‹‘ƒ†–Š‡‡ˆˆ‡ –•‘ˆ͵ͺ‘CYP11B2‡š’”‡••‹‘Ȍ

11.1.3Project3(Section7.3) ǤǤ‡‹‡”ǡ ǤƒŽ‡†ƒǡǤ‡‹†‡Žǡƒ†Ǥ Ǥ Š‘ŽŽǡDzͳ ͳͷͶͻ—–ƒ– ƒŽ ‹— Šƒ‡Ž ƒ—•‡•ƒ—–‘‘‘—•ƒŽ†‘•–‡”‘‡’”‘†— –‹‘‹ ͳͷ ‡ŽŽ•ƒ†‹•‹Š‹„‹–‡†„› ‹„‡ˆ”ƒ†‹Žǡdz†‘ ”‹‘Ž‘‰›ǡ˜‘ŽǤͳͷ͹ǡ‘Ǥͺǡ’’Ǥ͵Ͳͳ͸Ȃ͵ͲʹʹǡʹͲͳ͸Ǥ

•–Š‡”‡‹‡”ǯ• ‘–”‹„—–‹‘–‘–Š‡’—„Ž‹ ƒ–‹‘ǣ̱͹ͲΨȋ Ž‘‹‰ǡ’‡”ˆ‘”ƒ ‡ƒ††ƒ–ƒ ƒƒŽ›•‹•‘ˆ‡š’‡”‹‡–•–‘–‡•––Š‡‡ˆˆ‡ –•‘ˆCACNA1HM1549V‘CYP11B2‡š’”‡••‹‘ ƒ†ƒŽ†‘•–‡”‘‡’”‘†— –‹‘™‹–Š‹‘”Š‡Ž’„›”‹ ‡‹†‡Žƒ† —†”—ƒŽ‡†ƒȌ



ͻ͸ ϭϭƉƉĞŶĚŝdž 11.1.4Project4(Section7.4) Unpublished

•–Š‡” ‡‹‡”ǯ• ‘–”‹„—–‹‘•ǣ ‡‡”ƒ–‹‘ ‘ˆ ’͸Ǧ–”›ǦCACNA1H S1073Cƒ† ’͸ǦǦCACNA1HS1073Ǧ Ǧ Ǧ—”‘ǡ’‡”ˆ‘”ƒ ‡ƒ††ƒ–ƒƒƒŽ›•‹•ˆ‘”‡š’‡”Ǧ ‹‡–•–‡•–‹‰–Š‡‡ˆˆ‡ –•‘ˆͳ ͳͲ͹͵‘CYP11B2‡š’”‡••‹‘ǡ’‡”ˆ‘”ƒ ‡ ƒ††ƒ–ƒƒƒŽ›•‹•‘ˆ‡š’‡”‹‡–•–‘–‡•––Š‡‡ˆˆ‡ –•‘ˆͳ ͳͲ͹͵‘ƒŽ†‘•–‡”‘‡ ’”‘†— –‹‘–‘‰‡–Š‡”™‹–Š‡„‡”•‘ˆ ‡Ž‹š‡—• ŠŽ‡‹ǯ•‰”‘—’ȋ’‡”ˆ‘”ƒ ‡ƒ†ƒƒŽǦ ›•‹•‘ˆƒŽ†‘•–‡”‘‡ „›–Š‡‰”‘—’‘ˆ ‡Ž‹š‡—• ŠŽ‡‹ǡŽ‹‹—†‡”‹˜‡”•‹–¡– ò Š‡ǡ’‡”ˆ‘”ƒ ‡‘ˆ–”ƒ•ˆ‡ –‹‘ǡ–”‡ƒ–‡–ǡŠƒ”˜‡•–ƒ•™‡ŽŽƒ•’‡”ˆ‘”ƒ ‡ƒ† ƒƒŽ›•‹•‘ˆ’”‘–‡‹ƒ••ƒ›„›•–Š‡”‡‹‡”Ȍ

††‹–‹‘ƒŽ ‘–”‹„—–‹‘•„›‘–Š‡”•‡–‹‘‡†‹–Š‹•™‘”ǣ’ƒ–‹‡–•ǡ‰‡‡–‹ ƒƒŽ›•‹•ǡ insilicoƒƒŽ›•‹•‘ˆ—–ƒ–‹‘•„›ƒ”ƒŠƒ›‡ǡ‡–•—”‘‘•Š‹†ƒǡŠ‘ƒ• Š™ƒ”œƒ›”ǡ ƒ”–‹ ‹†Ž‹‰ƒ‹‡”ǡ ƒ”–‹ ‡‹ ‡ǡ ‹Ǧƒ––Š‹ƒ• –”‘ǡ ‹–•—Š‹†‡ ƒ”—•‡ǡ ‡Ž‹š ‡—• ŠŽ‡‹ǡ‡Ž‡ –”‘’Š›•‹‘Ž‘‰›„› ƒ„”‹‡Ž–ÚŽ–‹‰ǡ ‘”• Š—‰•œ‡–”— òŽ‹ Š



ͻ͹ ϭϭƉƉĞŶĚŝdž 11.2Plasmidmaps ƒ’•‘ˆ–Š‡‘•–‹’‘”–ƒ–’Žƒ•‹†•—•‡†‹–Š‹•™‘”ǡ‰‡‡”ƒ–‡†™‹–Š‡”‹ƒŽŽ‘‡” ʹǤ͸Ǥͳ

 &ŝŐƵƌĞϭϬ͘WůĂƐŵŝĚŵĂƉŽĨƉ/Z^ϮͲ<E:ϱͲĞ'&W͘



ͻͺ ϭϭƉƉĞŶĚŝdž

 &ŝŐƵƌĞϭϭ͘WůĂƐŵŝĚŵĂƉƉDsϲͲͲEϭ,Ͳ/Z^Ͳ'&WͲWƵƌŽ͘

11.3SequencingPrimers Š‡ ˆ‘ŽŽ‘™‹‰ ’”‹‡”• ™‡”‡ —•‡† ˆ‘” ƒ‰‡” •‡“—‡ ‹‰ ‘ˆ CACNA1H ‹–Š‹• ™‘”Ǥ dĂďůĞϱ͘WƌŝŵĞƌƐƵƐĞĚĨŽƌƉůĂƐŵŝĚƐĞƋƵĞŶĐŝŶŐ͘ůůƉƌŝŵĞƌƐƚĂƌŐĞƚƚŚĞŚƵŵĂŶĐE͘ ”‹‡” ‡“—‡ ‹‰–ƒ”‰‡– ‡“—‡ ‹‰ ”‹‡”•‡“—‡ ‡ ƒ‡ †‹”‡ –‹‘ ͳ Ǧ•‡“Ͳ —ƒ ͳ  ”˜     ͳ Ǧ•‡“ͳ —ƒ ͳ  ˆ™       ͳ Ǧ•‡“ʹ —ƒ ͳ  ˆ™          ͳ Ǧ•‡“͵ —ƒ ͳ  ˆ™        ͳ Ǧ•‡“Ͷ —ƒ ͳ  ˆ™      ͳ Ǧ•‡“ͷ —ƒ ͳ  ˆ™       ͳ Ǧ•‡“͸ —ƒ ͳ  ˆ™       ͳ Ǧ•‡“͹ —ƒ ͳ  ˆ™       ͳ Ǧ•‡“ͺ —ƒ ͳ  ˆ™       ͳ Ǧ•‡“ͻ —ƒ ͳ  ˆ™        

ͻͻ ϭϭƉƉĞŶĚŝdž 11.4Softwareusedforthegenerationofthisthesis Š‹•–Š‡•‹•™ƒ•™”‹––‡‹‹ ”‘•‘ˆ–‘”†ȋ‹ ”‘•‘ˆ–ǡ‡†‘†ǡǡȌǤ ˆ‘–‹†‹Ǧ ƒ–‡†‘–Š‡”™‹•‡ǡˆ‹‰—”‡•™‡”‡ ”‡ƒ–‡†—•‹‰ • ƒ’‡ȋ ”‡‡‘ˆ–™ƒ”‡ ‘—†ƒ–‹‘ǡ‘•Ǧ –‘ǡǡȌƒ†‹ ”‘•‘ˆ–‘™‡”‘‹–Ǥ‡”‹ƒŽŽ‘‡”ʹǤ͸Ǥͳȋ‡”‹ƒŽƒ•‹ •Ȍ™ƒ•—•‡† ˆ‘”–Š‡ƒƒ‰‡‡–‘ˆ’Žƒ•‹†•ƒ† Ž‘‹‰ǤŽƒ•‹†ƒ’•‹ Ž—†‡†‹–Š‹•™‘”™‡”‡ ‰‡‡”ƒ–‡†™‹–Š–Š‹•’”‘‰”ƒǤ

11.5SummaryofAPAstudies Š‡ˆ‘ŽŽ‘™‹‰–ƒ„Ž‡••—ƒ”‹œ‡—‡”‘—••–—†‹‡•‹˜‡•–‹‰ƒ–‹‰—–ƒ–‹‘•‹•ƒ† ˆ‹†‹‰•™‹–Š”‡‰ƒ”†–‘’ƒ–‹‡–ƒ†–—‘” Šƒ”ƒ –‡”‹•–‹ •Ǥ

ͳͲͲ dĂďůĞϲ͘^ƚƵĚŝĞƐŽĨ<E:ϱŵƵƚĂŶƚWƐ͘ĚĂƉƚĞĚĨƌŽŵ^ƚŽǁĂƐƐĞƌĞƚĂů͘ϮϬϭϯϯϱϭ͘

Study Region Mutation frequencies Characteristics of patients and tumors with KCNJ5 mutation Sex Age APA PHA Histology Comments size severity ‡”•–”ڏǡ ǡ Ͷ͸Ǥ͵Ψ ͳͷͳǣʹͶǤͺΨȋͺͶȀ͵͵ͻȌ ˆ‡ƒŽ‡„Ȁ Ȁ  Ȁ Ȁ ƒ‘˜‡”Žƒ’™‹–Š‡”•–”ڏǡ ʹͲͳʹƒǡʹͷͳ ȋͳͷ͹Ȁ͵͵ͻȌ ͳ͸ͺǣʹͲǤͻΨȋ͹ͳȀ͵͵ͻȌ ʹͲͳͷ ͳͶͷǣͲǤ͸ΨȋʹȀ͵͵ͻȌ „ ‘’ƒ”‡†–‘™– ›‘—‰‡”ȀŽƒ”‰‡”‹ƒŽ‡• ™‹–Š‘—–Š›’‡”’Žƒ•‹ƒ ‡”•–”ڏǡ ǡ ͷͶǤͷΨ Ȁ ˆ‡ƒŽ‡„›‘—‰‡”„Ȁ„ Ȁ Ȁ ƒ‘˜‡”Žƒ’™‹–Š‡”•–”ڏ ʹͲͳͷƒǡʹͶͻ ȋͻͲȀͳ͸ͷȌ ʹͲͳʹ „ ‘’ƒ”‡†–‘‘Ǧ ͷ —–ƒ– ”‡•‡ǡ  ͵ͷǤ͹Ψ ͳͷͳǣʹͳǤͶΨȋ͸ȀʹͺȌ Ȁƒ Ȁƒ Ȁ Ž‘™‡”ƒǡ„ Ȁ ƒ ‘’ƒ”‡†–‘™– ʹͲͳ͵ʹ͹ʹ ȋͳͲȀʹͺȌ ͳ͸ͺǣͳͶǤ͵ΨȋͶȀʹͺȌ „Ž‘™‡”•›•–‘Ž‹ ƒ† †‹ƒ•–‘Ž‹ „Ž‘‘†’”‡••—”‡ œ‹œƒǡ ǡ ͶͳǤͳΨ ͳͷͳʹ͸ǤͲΨȋͳͻȀ͹͵Ȍ Ȁ Ȁ Žƒ”‰‡”ƒ Ȁ Ȁ ƒ ‘’ƒ”‡†–‘™– ʹͲͳʹʹͷͻ ȋ͵ͲȀ͹͵Ȍ ͳ͸ͺͳ͵Ǥ͹ΨȋͳͲȀ͹͵Ȍ ͳͷ͹†‡ŽͳǤͶΨȋͳȀ͹͵Ȍ ‘—Ž”‘—ǡ  ͵͵ǤͻΨ ͳͷͳǣʹͲΨȋ͹͸Ȁ͵ͺͲȌ ˆ‡ƒŽ‡ƒ›‘—‰‡”ƒȀƒŠ‹‰Š‡”ƒǡ„Ȁ ƒ ‘’ƒ”‡†–‘™– ʹͲͳʹʹͶ͸ ȋͳʹͻȀ͵ͺͲȌ ͳ͸ͺǣͳ͵ǤͻΨȋͷ͵Ȁ͵ͺͲȌ „Š‹‰Š‡”

Š‡‰ǡʹͲͳͷͳͻͺ  ͵͹Ǥ͹Ψ ͳͷͳǣͳͷǤͻΨȋͳͳȀ͸ͻȌ ˆ‡ƒŽ‡ƒ›‘—‰‡”ƒŽƒ”‰‡”ƒȀƒǡ„Ȁ ƒ ‘’ƒ”‡†–‘™– ȋʹ͸Ȁ͸ͻȌ ͳ͸ͺǣͳ͵ΨȋͻȀ͸ͻȌ „ȀŽ‘‘†’”‡••—”‡ ͳͶͷǣͳǤͶΨȋͳȀ͸ͻȌ ͳͳͷǣͶǤ͵Ψȋ͵Ȁ͸ͻȌ ʹͶ͸ ǣʹǤͻΨȋʹȀ͸ͻȌ Š‘‹ǡʹͲͳͳƒǡͳͻ͹  ͵͸ǤͶΨ ͳͷͳǣͻǤͳΨȋʹȀʹʹȌ ˆ‡ƒŽ‡„ ›‘—‰‡”„ Ȁ Ȁ Ȁ ƒ‘˜‡”Žƒ’™‹–Š Š‘ŽŽǡʹͲͳ͵ ȋͺȀʹʹȌ ͳ͸ͺǣʹ͹Ǥ͵Ψȋ͸ȀʹʹȌ „ƒ ‘”†‹‰–‘ Š‘ŽŽƒ† ‹ˆ–‘ǡʹͲͳ͵ʹ͵͹ ϭ Ϭϭ  Study Region Mutation frequencies Characteristics of patients and tumors with KCNJ5 mutation Sex Age APA PHA Histology Comments size severity ‡‡”•ǡ  ͶͳǤͷΨ ͳͷͳǣͳͺǤͻΨȋͳͲȀʹʹȌƒ ˆ‡ƒŽ‡„Ȁ  Ȁ Ȁ  ǦŽ‹‡  ƒͳ—Ž–‹‘†—Žƒ” ʹͲͳͶʹͷ͸ ȋʹʹȀͷ͵Ȍ ͳ͸ͺǣʹʹǤ͸ΨȋͳʹȀʹʹȌƒ Š›’‡”’Žƒ•‹ƒ™‹–Šʹ‘†—Ž‡• ͳͷͶͷǣͳǤͻΨȋͳȀʹʹȌ ‘–ƒ‹‹‰†‹ˆˆ‡”‡–KCNJ5 —–ƒ–‹‘• „ ‘’ƒ”‡†–‘ƒŽ‡ ‘’ƒ”‡†–‘™– —––ƒǡʹͲͳͶʹ͹͵  ͵ͳǤͶΨ ͳͷͳǣʹʹǤͻΨȋͺȀ͵ͷȌ ͹Ȁͳͳ Ȁƒ ȀƒȀƒǡ„Ȁ ƒ ‘’ƒ”‡†–‘™–ƒ† ȋͳͳȀ͵ͷȌ ͳ͸ͺǣͺǤ͸Ψȋ͵Ȁ͵ͷȌ ˆ‡ƒŽ‡ †‹ˆˆ‡”‡–—–ƒ–‰”‘—’• „ ‡”ƒ†‡•Ǧ  ͵ͺΨ ͳͷͳǣʹ͵ǤͺΨ ˆ‡ƒŽ‡„Ȁ„Ȁ„ǡ  Ȁ Ȁ† ƒˆ‘”’ƒ–‹‡– Šƒ”ƒ –‡”‹•–‹ • ‘•ƒǡʹͲͳͶʹ͸ʹ ȋͳͺͲȀͶ͹ͶȌƒ ȋͳͳ͵ȀͶ͹ͶȌ ‘Ž›͵͸ͷ• ͳ͸ͺǣͳ͵Ǥ͹Ψȋ͸ͷȀͶ͹ͶȌ „ ‘’ƒ”‡†–‘™– ͳͷͺǣͲǤʹΨȋͳȀͶ͹ͶȌ ‘’ƒ”‡†–‘CACNA1D ͳʹ͸ǣͲǤʹΨȋͳȀͶ͹ͶȌ —–ƒ– †͹ͺ•ǡ ‘’ƒ”‡†ƒ ”‘•• ‰”‘—’• ‘‰ǡʹͲͳ͸ʹ͹Ͷ  ͹ͳǤʹΨ ͳͷͳǣͶ͹Ψȋ͵ͳȀ͸͸Ȍ ˆ‡ƒŽ‡ƒ›‘—‰‡”ƒǡ„ ȀƒȀƒǡ Ȁ ƒ ‘’ƒ”‡†–‘™– ȋͶ͹Ȁ͸͸Ȍ ͳͷͺǣʹͶǤʹΨȋȋͳ͸Ȁ͸͸Ȍ „Š‹‰Š‡”’‘”–‹‘—†‡”͵ͷǡ ‘†‹ˆˆ‡”‡ ‡‹ƒ‰‡ ǡ„Ž‘‘†’”‡••—”‡ ‹–ƒ‘–‘ǡ  ͸ͻǤͶΨ ͳͷͳͶʹǤ͸ΨȋͶ͸ȀͳͲͺȌ Ȁƒ ›‘—‰‡”ƒŽƒ”‰‡”ƒŠ‹‰Š‡”ƒȀ ƒ ‘’ƒ”‡†–‘™– ʹͲͳͷʹͶͺ ȋ͹ͷȀͳͲͺȌ ͳ͸ͺʹʹǤʹΨȋʹͶȀͳͲͺȌ „ǡ—”‹ƒ”›ƒŽ†‘•–‡”‘‡ ͳͶͷͳǤͻΨȋʹȀͳͲͺȌ ͳͷͺͲǤͻΨȋͳȀͳͲͺȌ ͳͷ͹†‡ŽͳǤͻΨȋʹȀͳͲͺȌ —’’—•ƒ›ǡ  ʹͶǤ͸Ψ ͳͷͳͳ͵ǤͺΨȋʹ͹ȀͳͻͷȌ Ȁ Ȁ Ȁ Ȁ Ȁ ʹͲͳͶʹ͸͸ ȋͶͺȀͳͻͷȌ ͳ͸ͺͺǤ͹Ψȋͳ͹ȀͳͻͷȌ ͳͷͺͳǤͷΨȋ͵ȀͳͻͷȌ ‹•ͳͶͻͲǤͷΨȋͳȀͳͻͷȌ ‘–‹ ‘‡ǡ ǡǡ ͵ͺǤ͵Ψ ͳͷͳͳ͹ΨȋͺȀͶ͹Ȍ ˆ‡ƒŽ‡ƒȀƒ Ȁ Ȁƒǡ„ Ȁ ƒ ‘’ƒ”‡†–‘™– ʹͲͳʹʹͷͲ  ȋͳͺȀͶ͹Ȍ ͳ͸ͺʹͳǤ͵ΨȋͳͲȀͶ͹Ȍ „ǡ„Ž‘‘†’”‡••—”‡ ϭ ϬϮ  Study Region Mutation frequencies Characteristics of patients and tumors with KCNJ5 mutation Sex Age APA PHA Histology Comments size severity  Š‘ŽŽǡ ǡ ͵ʹǤͺΨ ͳͷͳǣͳͺǤͺΨȋͳʹȀ͸ͶȌ ͳͷȀʹͳ Ȁ Ȁ Ȁ Ȁ ƒ‘˜‡”Žƒ’™‹–ŠŠ‘‹ǡʹͲͳͳ ʹͲͳ͵ƒǡͳʹͳ ȋʹͳȀ͸ͶȌ ͳ͸ͺǣͳͶǤͳΨȋͻȀ͸ͶȌ ˆ‡ƒŽ‡ ƒ‰— Š‹ǡ  ͸ͷǤʹΨ ͳͷͳǣͷʹǤʹΨȋͳʹȀʹ͵Ȍ ͺȀͳͷˆ‡ƒŽ‡ Ȁ Ȁ Ȁ Ȁ ʹͲͳʹʹͷͶ ȋͳͷȀʹ͵Ȍ ͳ͸ͺǣͳ͵ǤͲΨȋ͵Ȁʹ͵Ȍ ‹ŽŽ‹ƒ•ǡ  ͵ͻǤ͵Ψ ͳͷͳǣ͵ͳǤ͵Ψȋ͵ͷȀͳͳʹȌ ˆ‡ƒŽ‡ƒȀ„Ȁ„Ȁ„Ȁ ƒƒŽ‡˜•Ǥˆ‡ƒŽ‡ ʹͲͳ͵ʹ͹ͷ ȋͶͶȀͳͳʹȌ ͳ͸ͺǣͺǤͻΨȋͳͲȀͳͳʹȌ „ ‘’ƒ”‡†„‡–™‡‡ ͳͷͺǣͲǤͻΨȋͳȀͳͳʹȌ ‰”‘—’• ͳʹ͸ǣͲǤͻΨȋͳȀͳͳʹȌ —ǡʹͲͳͷʹ͸͹  ͷͻǤͷΨ ͳͷͳǣ͵ͲǤͶΨȋͶͷȀͳͶͺȌ Ȁ Ȁ Ȁ Ȁ Ȁ ȋͺͺȀͳͶͺȌ ͳ͸ͺǣʹ͹Ǥ͹ΨȋͶͳȀͳͶͺȌ ͳͷ͹†‡ŽǣͲǤ͹ΨȋͳȀͳͶͺȌ ͳͷͺǣͲǤ͹ΨȋͳȀͳͶͺȌ —ǡʹͲͳ͹ʹ͹͸  ͷ͵Ψ ͳͷͳ ʹͻΨȋ͸ͶȀʹͳͻȌ Ȁ Ȁ Ȁ Ȁ Ȁ ȋͳͳ͸ȀʹͳͻȌ ͳ͸ͺ ʹͳǤͻΨȋͶͺȀʹͳͻȌ ͳͷͺͳǤͶΨȋ͵ȀʹͳͻȌ ͳͷ͹†‡ŽͲǤͷΨȋͳȀʹͳͻȌ ‡‘—‹ǡ  ͳʹǤͷΨ ͳͷͳǣͳʹǤͷΨȋʹȀͳ͸Ȍ ƒŽŽˆ‡ƒŽ‡ Ȁ Ȁ Ȁ Ȁ ʹͲͳʹʹ͹͹ ȋʹȀͳ͸Ȍ Š‡‰ǡʹͲͳͷʹͷ͵  ͹͸ǤͺΨ ͳͷͳ͵ͻǤͻΨȋ͸͹Ȁͳ͸ͺȌ ˆ‡ƒŽ‡ƒȀƒ Žƒ”‰‡”ƒŠ‹‰Š‡”ƒȀ ƒ ‘’ƒ”‡†–‘™– ȋͳʹͻȀͳ͸ͺȌ ͳ͸ͺǣ͵ͷǤ͹Ψȋ͸ͲȀͳ͸ͺȌ ͳͷͺǣͲǤ͸ΨȋͳȀͳ͸ͺȌ ͳͶͺǦͳͶͻ‹•ͲǤ͸Ψ ȋͳȀͳ͸ͺȌ Ȁǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ǡȀǣ‘†‹ˆˆ‡”‡ ‡ǡǣ—•–”ƒŽ‹ƒǡǣƒ•–•‹ƒǡǣ—”‘’‡ǡǣ‘”–Š‡”‹ ƒǡǣ’Žƒ•ƒƒŽ†‘•–‡”‘‡ ‘ ‡–”ƒ–‹‘ ϭ Ϭϯ  dĂďůĞϳ͘^ƚƵĚŝĞƐŽĨEϭŵƵƚĂŶƚWƐ͘>ĂLJŽƵƚĂĚĂƉƚĞĚĨƌŽŵ^ƚŽǁĂƐƐĞƌĞƚĂů͘ϮϬϭϯϯϱϭ͘ Study Region Mutation frequencies Characteristics of patients and tumors with CACNA1D mutation Sex Age APA PHA Histology Comments size severity ‡”•–”ڏǡ ǡ ͵ΨȋͷȀͳ͸ͷȌ ͶͲ͵ǣͳǤʹΨȋʹȀͳ͸ͷȌ ͵ȀͷƒŽ‡ƒȀƒ Ȁƒ Ȁ Ȁ ƒƒŽ‡ǡ‘Ž†‡”ƒ†•ƒŽŽ‡” ʹͲͳͷʹͶͻ Ͷ͹ͶǣͲǤ͸ΨȋͳȀͳ͸ͷȌ ˆ‘”CACNA1DΪƒ•‡ ͳ͵ͷ͵ǣͲǤ͸ΨȋͳȀͳ͸ͷȌ ‘’ƒ”‡†–‘KCNJ5 ͶͲͳǣͲǤ͸ΨȋͳȀͳ͸ͷȌ œ‹œƒǡ  ͹ǤͻΨ ͶͲ͵ͳǤ͵Ψȋʹ ͳͷʹȌ ͳͲȀͳʹ Ȁƒ Ȁƒ Ȁ Ȁƒ ƒƒŽ‡ǡ‘Ž†‡”ǡ•ƒŽŽ‡”ƒ† ʹͲͳ͵ʹ͸ͻ ȋͳʹȀͳͷʹȌ ʹͷͻͳǤ͵ΨȋʹȀͳͷʹȌ ƒŽ‡ƒ  ǦŽ‹‡ˆ‘”CACNA1DΪ ͹Ͷ͹ͳǤ͵ΨȋʹȀͳͷʹȌ ƒ•‡ ‘’ƒ”‡†–‘ ͹ͷͲͳǤ͵ΨȋʹȀͳͷʹȌ KCNJ5 ͳ͵͵͸ͳǤ͵ΨȋʹȀͳͷʹȌ ͳ͵ͷͶ ͲǤ͹ΨȋͳȀͳͷʹȌ ͻͻͲ ͲǤ͹ΨȋͳȀͳͷʹȌ ‡‡”•ǡ  ͳǤͻΨ ͳ͹ͷͲǣͳǤͻΨȋͳȀͷ͵Ȍ ͳȀͳƒŽ‡ Ȁ Ȁ Ȁ  ǦŽ‹‡ ʹͲͳͶʹͷ͸ ȋͳȀͷ͵Ȍ ϭ Ϭϰ  Study Region Mutation frequencies Characteristics of patients and tumors with CACNA1D mutation Sex Age APA PHA Histology Comments size severity ‡”ƒ†‡•Ǧ  ͻǤ͵Ψ ͶͲ͵ȋͺΪͺȌǣʹǤ͵Ψ ƒŽ‡„ǡ ‘Ž†‡”„ǡ  •ƒŽŽ‡”ƒǡ Š‹‰Š‡”„ǡ ǡ‡Ȁƒǡ„ǡ  ƒ ‘’ƒ”‡†–‘™– ‘•ƒǡʹͲͳ͵ʹ͸ʹ ȋͶͶȀͶ͹ͶȌ ȋͳͳȀͶ͹ͶȌ „ǡ ǡȀ† „ ‘’ƒ”‡†–‘KCNJ5 ͹Ͷ͹ǣͳǤ͵Ψȋ͸ȀͶ͹ͶȌ ͹ͺ•ǡƒ”‹• ‘Š‘”– ͳ͵͵ͺǣͳǤ͵Ψȋ͸ȀͶ͹ͶȌ † ‘’ƒ”‡†–‘™–ƒ† ͹ͷͲǣͲǤͺΨȋͶȀͶ͹ͶȌ KCNJ5 ‹͵͸ͷ•ˆ”‘͵ ͻͻͺ ǣͲǤ͸Ψȋ͵ȀͶ͹ͶȌ ‘Š‘”–• ͳͳͷͳ ǣͲǤʹΨȋʹȀͶ͹ͶȌ ‡•›•–‘Ž‹ „Ž‘‘†’”‡••—”‡ ʹͷͻǣͲǤʹΨȋͳȀͶ͹ͶȌ ͸ͷʹǣͲǤʹΨȋͳȀͶ͹ͶȌ ͸ͷͷǣͲǤʹΨȋͳȀͶ͹ͶȌ ͹ͶͳǣͲǤʹΨȋͳȀͶ͹ͶȌ ͹Ͷ͹ǣͲǤʹΨȋͳȀͶ͹ͶȌ ͹ͷͲ ǣͲǤʹΨȋͳȀͶ͹ͶȌ ͻ͹ͻǣͲǤʹΨȋͳȀͶ͹ͶȌ ͻͺͳǣͲǤʹΨȋͳȀͶ͹ͶȌ ͻͻͺǣͲǤʹΨȋͳȀͶ͹ͶȌ ͳͳͷʹǣͲǤʹΨȋͳȀͶ͹ͶȌ ͳ͵͵͸ǣͲǤʹΨȋͳȀͶ͹ͶȌ ͳ͵ͷͶ ǣͲǤʹΨȋͳȀͶ͹ͶȌ ‹–ƒ‘–‘ǡ  ʹǤͷΨ ͶͲ͵ǣͳǤͻΨȋ͵ȀͳͷͻȌ Ȁƒ ȀƒȀƒȀƒ ǦŽ‹‡  ƒ ‘’ƒ”‡†–‘™– ʹͲͳ͸ʹͷͷ ȋͶȀͳͷͻȌ ͹ͷͲǣͲǤ͸ΨȋͳȀͳͷͻȌ •‹‹Žƒ”–‘™–  Š‘ŽŽǡʹͲͳ͵ͳʹͳ ǡ ͳͲǤͻΨ ͶͲ͵ȋͺΪͺȌǣ͸Ǥ͵Ψ Ȁƒ Ȁ„ •ƒŽŽ‡”„ Ȁ Ȁ ƒ‘–‡†‡ ›†‡–‡ –‡† ȋ͹Ȁ͸ͶȌ ȋͶȀ͸ͶȌ „ ‘’ƒ”‡†–‘KCNJ5 ͹ͷͲͳǤ͸ΨȋͳȀ͸ͶȌ ͹Ͷ͹ͳǤ͸ΨȋͳȀ͸ͶȌ ͳ͵͹͵ͳǤ͸ΨȋͳȀ͸ͶȌ Š‡‰ǡʹͲͳͷʹͷ͵  ͲǤ͸Ψ ͶͲ͵ǣͲǤ͸ΨȋͳȀͳ͸ͺȌ Ȁ Ȁ Ȁ Ȁ Ȁ ȋͳȀͳ͸ͺȌ Ȁǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ǡȀǣ‘†‹ˆˆ‡”‡ ‡ǡǣ—•–”ƒŽ‹ƒǡǣƒ•–•‹ƒǡǣ—”‘’‡ǡǣ‘”–Š‡”‹ ƒ ϭ Ϭϱ  dĂďůĞϴ͘^ƚƵĚŝĞƐŽĨdWĂƐĞŵƵƚĂŶƚWƐ͘>ĂLJŽƵƚĂĚĂƉƚĞĚĨƌŽŵ^ƚŽǁĂƐƐĞƌĞƚĂů͘ϮϬϭϯϯϱϭ͘ Study Region Mutation frequencies Characteristics of patients and tumors with ATPase mutation Sex Age APA PHA Histology Comments size severity ‡”•–”ڏǡ ǡ ͻǤͳΨ ͳͳǣ͸ǤͳΨȋͳͲȀͳ͸ͷȌ ͳͲȀͳͷ Ȁƒ ȀƒȀ„Ȁ ƒƒŽ‡ǡ‘Ž†‡”ƒ†•ƒŽŽ‡”ˆ‘” ʹͲͳͷʹͶͻ ȋͳͷȀͳ͸ͷȌ ͳͲͶʹǤͶΨȋͶȀͳ͸ͷȌ ƒŽ‡ƒ CACNA1DΪƒ•‡ ͳͲʹ̴ ͳͲ͸†‡ŽͲǤ͸Ψ ‘’ƒ”‡†–‘KCNJ5 ȋͳȀͳ͸ͷȌ „‘†‹ˆˆ‡”‡ ‡‹Ž‡˜‡Ž• ͻͷͻ̴ ͻ͸ͳ†‡ŽͲǤ͸Ψ ˆ‘” CACNA1D Ϊƒ•‡ ȋͳȀͳ͸ͷȌ ‘’ƒ”‡†–‘KCNJ5 ͻ͸Ͳ̴ͻ͸Ͷ†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ ͻͷ͸̴ ͻ͸ͳ†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ ͳͲʹ̴ͳͲ͵†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ ͳͲ͵̴ͳͲͶ†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ ʹ͵͵ΨȋͷȀͳ͸ͷȌ ͶʹͶǦͶʹͷ†‡ŽͳǤʹΨ ȋʹȀͳ͸ͷȌ Ͷʹ͵ǦͶʹͷ†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ ͶʹͶǦͶʹ͸†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ Ͷʹ͸ǦͶʹͻ†‡ŽͲǤ͸Ψ ȋͳȀͳ͸ͷȌ œ‹œƒǡʹͲͳ͵ʹ͸ͻ  ͹ǤͻΨ ͳͳ͹ǤͻΨȋͳʹȀͳͷʹȌ ͳͳȀͳʹ Ȁƒ Ȁƒ Ȁ Ȁƒ ƒƒŽ‡ǡ‘Ž†‡”ǡ•ƒŽŽ‡”ƒ† ȋͳʹȀͳͷʹȌ ͳͲͶ͸Ǥ͸ΨȋͳͲȀͳͷʹȌ ƒŽ‡ƒ  ǦŽ‹‡ˆ‘”CACNA1DΪ ͳͲͲ̴ͳͲͶ†‡ŽͲǤ͹Ψ ƒ•‡ ‘’ƒ”‡†–‘KCNJ5 ȋͳȀͳͷʹȌ ͻ͸͵ͲǤ͹ΨȋͳȀͳͷʹȌ ϭ Ϭϲ  Study Region Mutation frequencies Characteristics of patients and tumors with ATPase mutation Sex Age APA PHA Histology Comments size severity ‡—• ŠŽ‡‹ǡ  ͸ǤͺΨ ͳͳͷǤʹΨȋͳ͸Ȁ͵ͲͺȌ ƒŽ‡ƒ ‘Ž†‡”ƒǡ„Ȁƒǡ„ǡ Š‹‰Š‡” ǡ†Ȁ ƒ ‘’ƒ”‡†–‘KCNJ5 ʹͲͳ͵ʹͶͶ ȋʹͳȀ͵ͲͺȌ ͳͲͶǣ͵ǤͻΨȋͳʹȀ͵ͲͺȌ „’ƒ–‹‡–•ˆ”‘ʹ ‘Š‘”–• ͳͲͲ̴ͳͲͶ̴†‡ŽͳΨ ‘’ƒ”‡†–‘™– ȋ͵Ȁ͵ͲͺȌ † ͵͵ʹ ǣͲǤ͵ΨȋͳȀ͵ͲͺȌ ʹ͵ͳǤ͸ΨȋͷȀ͵ͲͺȌ Ͷʹͷ̴Ͷʹ͸̴†‡ŽǣͳǤ͵Ψ ȋͶȀ͵ͲͺȌ Ͷʹ͸̴Ͷʹ͹̴†‡ŽǣͲǤ͵Ψ ȋͳȀ͵ͲͺȌ ‡‡”•ǡ  ͳͳǤ͵Ψ ͳͳ ͷȀ͸ƒŽ‡ Ȁ ʹ͵ Ȁ  ǦŽ‹‡ ƒ ‘’ƒ”‡†–‘KCNJ5 ʹͲͳͶʹͷ͸ ȋ͸Ȁͷ͵Ȍ ͳͲͶǣͳǤͻΨȋͳȀͷ͵Ȍ •ƒŽŽ‡”ƒ ʹ͵ Ͷʹͷ̴Ͷʹ͸†‡ŽǣͻǤͶΨ ȋͷȀͷ͵Ȍ —––ƒǡʹͲͳͶʹ͹͵  ͳͶǤ͵Ψ ͳͳ ͶȀͷƒŽ‡ Ȁƒ ȀƒȀƒǡ„Ȁ ƒ„‡–™‡‡™–ƒ††‹ˆˆ‡”‡– ȋͷȀ͵ͷȌ ͳͲͶǣͷǤ͹ΨȋʹȀ͵ͷȌ —–ƒ–‰”‘—’• ʹ͵ǣͺǤ͸Ψȋ͵Ȁ͵ͷȌ „ Ͷʹͷ̴Ͷʹ͸†‡ŽǣͷǤ͹Ψ ȋʹȀ͵ͷȌ Ͷʹͺ̴Ͷʹͻ†‡ŽǣʹǤͻΨ ȋͳȀ͵ͷȌ ϭ Ϭ ϳ Study Region Mutation frequencies Characteristics of patients and tumors with ATPase mutation Sex Age APA PHA Histology Comments size severity ‡”ƒ†‡•Ǧ  ͹Ψ ͳͳͷǤ͵ΨȋʹͷȀͶ͹ͶȌ Ȁ Ȁ Ȁ Ȁ Ȁ ‘•ƒǡʹͲͳͶʹ͸ʹ ȋ͵͵ȀͶ͹ͶȌ ͳͲͶ͵Ǥ͸Ψȋͳ͹ȀͶ͹ͶȌ ͳͲͲ̴ͳͲͶ†‡ŽͳǤͳΨ ȋͷȀͶ͹ͶȌ ͵͵ʹ ͲǤͶΨȋʹȀͶ͹ͶȌ ͻͻͲǤʹΨȋͳȀͶ͹ͶȌ ʹ͵ͳǤ͹ΨȋͺȀͶ͹ͶȌ Ͷʹͷ̴Ͷʹ͸†‡ŽͳǤͳΨ ȋͷȀͶ͹ͶȌ ͶʹͶ̴Ͷʹͷ†‡ŽͲǤͶΨ ȋʹȀͶ͹ͶȌ Ͷʹ͸̴Ͷʹ͹†‡ŽͲǤʹΨ ȋͳȀͶ͹ͶȌ ‹–ƒ‘–‘ǡ  ͵ǤͳΨ ͳͳ ƒŽŽƒŽ‡ ›‘—‰‡”ƒ •ƒŽŽ‡”ƒŠ‹‰Š‡”ƒǡ„  ǦŽ‹‡ ƒ ‘’ƒ”‡†–‘™–ǡ–‡†‡ ‹‡• ʹͲͳ͸ʹͷͷ ȋͷȀͳͷͻȌ ͳͲͶͲǤ͸ΨȋͳȀͳͷͻȌ „Š‹‰Š—”‹ƒ”›ƒŽ†‘•–‡”‘‡ ʹ͵ʹǤͷΨȋͶȀͳͷͻȌ Ͷʹͷ̴Ͷʹ͸†‡ŽͳǤ͵Ψ ȋʹȀͳͷͻȌ Ͷʹ͹̴Ͷʹͺ†‡ŽͲǤ͸Ψ ȋͳȀͳͷͻȌ ͶʹͶ̴Ͷʹͷ†‡ŽͲǤ͸Ψ ȋͳȀͳͷͻȌ —’’—•ƒ›ǡ  ʹǤͳΨ ͳͳ Ȁ Ȁ Ȁ Ȁ Ȁ ʹͲͳͶʹ͸͸ ȋͶȀͳͻͷȌ ͳͲͶͳǤͷΨȋ͵ȀͳͻͷȌ ʹ͵ ͳʹ͸̴ͳʹ͹†‡ŽͲǤͷΨ ȋͳȀͳͻͷȌ ϭ Ϭ ϴ Study Region Mutation frequencies Characteristics of patients and tumors with ATPase mutation Sex Age APA PHA Histology Comments size severity  Š‘ŽŽǡʹͲͳ͵ͳʹͳ ǡ ͶǤ͹Ψ ͳͳ Ȁ Ȁ Ȁ Ȁ Ȁ ȋ͵Ȁ͸ͶȌ ͳͲͶͳǤ͸ΨȋͳȀ͸ͶȌ ʹ͵͵ǤͳΨȋʹȀ͸ͶȌ Ͷʹ͸̴Ͷʹ͹†‡ŽͳǤ͸Ψ ȋͳȀ͸ͶȌ Ͷʹͷ̴Ͷʹ͸†‡ŽͳǤ͸Ψ ȋͳȀ͸ͶȌ ‹ŽŽ‹ƒ•ǡ  ͹ǤͳΨ ͳͳǣ͸Ǥ͵Ψȋ͹ȀͳͳʹȌ Ȁƒ Ȁ„Ȁ„Ȁ„ǡ Ȁ ƒ ‘’ƒ”‡†ƒŽ‡–‘ˆ‡ƒŽ‡ ʹͲͳ͵ʹ͹ͷ ȋͺȀͳͳʹȌ ͳͲͶǣͷǤͶΨȋ͸ȀͳͳʹȌ „„‡–™‡‡™–ƒ††‹ˆˆ‡”‡– ͻͻǣͲǤͻΨȋͳȀͳͳʹȌ —–ƒ–‰”‘—’• ʹ͵ ǡǡ’”‡‘’‡”ƒ–‹˜‡ Ͷʹͷ̴Ͷʹ͸†‡ŽǣͲǤͻΨ „Ž‘‘†’”‡••—”‡ ȋͳȀͳͳʹȌ —ǡʹͲͳͷƒǡʹ͸͹  ʹΨȋ͵ȀͳͶͺȌ ͳͳ Ȁ Ȁ Ȁ Ȁ Ȁ ƒŽ‹‡Ž›‘˜‡”Žƒ’™‹–Š—ǡ ͳͲͶǣͳǤͶΨȋʹȀͳͶͺȌ ʹͲͳ͹ǡ„—–‘–•’‡ ‹ˆ‹‡† ʹ͵ ͶͳͲǣͲǤ͹ΨȋͳȀͳͶͺȌ —ǡʹͲͳ͹ƒǡʹ͹͸  ͳǤͺΨ ͳͳ Ȁ Ȁ Ȁ Ȁ Ȁ ƒŽ‹‡Ž›‘˜‡”Žƒ’™‹–Š—ǡ ȋͶȀʹͳͻȌ„ ͳͲͶǣͳǤͶΨȋ͵Ȁʹͳͻ„Ȍ ʹͲͳͷǡ„—–‘–•’‡ ‹ˆ‹‡† ʹ͵ „—„‡” ƒŽ —Žƒ–‡†ˆ”‘ ͶͳͲǤͲǤͷΨȋͳȀʹͳͻ„Ȍ ’‡” ‡–ƒ‰‡ Š‡‰ǡʹͲͳͷʹͷ͵  ͵Ψȋ͸Ȁͳ͸ͺȌ ͳͳǣʹǤͶΨȋͶȀͳ͸ͺȌ ƒŽŽƒŽ‡ Ȁ Ȁ Ȁ Ȁ ͳͲͶͳǤͺΨȋ͵Ȁͳ͸ͺȌ ͳͲʹ̴ͳͲ͵†‡ŽǣͲǤ͸Ψ ȋͳȀͳ͸ͺȌ ʹ͵ †‡ŽͶʹʹ̴Ͷʹ͸‹• ͲǤ͸ΨȋͳȀͳ͸ͺȌ Ȁǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ǡȀǣ‘†‹ˆˆ‡”‡ ‡ǡǣ—•–”ƒŽ‹ƒǡǣƒ•–•‹ƒǡǣ—”‘’‡ǡǣ‘”–Š‡”‹ ƒǡǣ’Žƒ•ƒ”‡‹ƒ –‹˜‹–›ǡǣ’Žƒ•ƒƒŽ†‘•–‡”‘‡ ‘ ‡–”ƒ–‹‘ ϭ Ϭ ϵ dĂďůĞϵ͘^ƚƵĚŝĞƐŽĨdEEϭŵƵƚĂŶƚWƐ͘>ĂLJŽƵƚĂĚĂƉƚĞĚĨƌŽŵ^ƚŽǁĂƐƐĞƌĞƚĂů͘ϮϬϭϯϯϱϭ͘ Study region Mutation frequencies Characteristics of patients and tumors with CTNNB1 mutation Sex Age APA PHA Histology Comment size severity ‡”•–”ڏǡ ǡ ͷǤͳΨ ͶͷͶǤͲΨȋͺȀͳͻͺȌ Ȁƒǡ„ Ȁƒǡ„Žƒ”‰‡”ƒȀƒǡ„Ȁ ƒ ‘’ƒ”‡†–‘™– ʹͲͳ͸ʹ͹ͳ ȋͳͲȀͳͻͺȌ Ͷͷ ͲǤͷΨȋͳȀͳͻͺȌ „ ‘’ƒ”‡†–‘KCNJ5 ͶͳͲǤͷΨȋͳȀͳͻͺȌ  Š‘ŽŽǡʹͲͳ͵ͳʹͳ ǡ ͵ǤͳΨ Ͷͷ͵ǤͳΨȋʹȀ͸ͶȌ ƒŽŽˆ‡ƒŽ‡ Ȁ Ȁ Ȁ Ȁ ȋʹȀ͸ͶȌ ƒ†Œ‹‡ǡʹͲͲͺʹͶͷ  ͻǤͳΨ ʹ͸ͻͻͷ†‡Žʹ͹ͳ„’ͻǤͳΨ ͳȀͳˆ‡ƒŽ‡ Ȁ Ȁ Ȁ Ȁ ȋͳȀͳͳȌ ȋͳȀͳͳȌ —ǡʹͲͳ͹ʹ͹͸  ͵Ǥ͹Ψ ͶͷʹǤ͵ΨȋͷȀʹͳͻ Ȁƒǡ„ ‘Ž†‡”„ȀĂ͕ďȀĂ͕ď͕ĐȀ ƒ ‘’ƒ”‡†–‘™– ȋͺȀʹͳͻȌ Ͷͷ ͳǤͶΨȋ͵ȀʹͳͻȌ „ ‘’ƒ”‡†–‘KCNJ5 „Ž‘‘†’”‡••—”‡ǡǡŽ‘‰ ǡŽ‘‰ Ȁǣ‘–ƒ˜ƒ‹Žƒ„Ž‡ǡȀǣ‘†‹ˆˆ‡”‡ ‡ǡǣ—•–”ƒŽ‹ƒǡǣƒ•–•‹ƒǡǣ—”‘’‡ǡǣ‘”–Š‡”‹ ƒǡǣ’Žƒ•ƒ”‡‹ƒ –‹˜‹–›ǡǣ’Žƒ•ƒƒŽ†‘•–‡”‘‡ ‘ ‡–”ƒ–‹‘ǡ ǣƒŽ†‘•–‡”‘‡Ǧ–‘Ǧ”‡‹”ƒ–‹‘ ϭ ϭ Ϭ ϭϮŝĚĞƐƐƚĂƚƚůŝĐŚĞƌŬůćƌƵŶŐ

12 EidesstattlicheErklärung Š˜‡”•‹ Š‡”‡ƒ‹†‡•–ƒ––ǡ†ƒ••†‹‡‹••‡”–ƒ–‹‘˜‘‹”•‡Ž„•–¡†‹‰—†‘Š‡—œ—Ǧ Ž¡••‹‰‡ ˆ”‡†‡ ‹Žˆ‡ —–‡” ‡ƒ Š–—‰ †‡” Ƿ ”—†•¡–œ‡ œ—” ‹ Š‡”—‰ ‰—–‡” ™‹••‡Ǧ • Šƒˆ–Ž‹ Š‡””ƒš‹•ƒ†‡” ‡‹”‹ ŠǦ ‡‹‡Ǧ‹˜‡”•‹–¡–ò••‡Ž†‘”ˆDz‡”•–‡ŽŽ–™‘”†‡‹•–Ǥ

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ò••‡Ž†‘”ˆǡͲʹǤͲʹǤʹͲͳͺ

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