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Kohdennettu Uuden Sukupolven DNA-Sekvensointi

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Kohdennettu Uuden Sukupolven DNA-Sekvensointi HELSINGIN YLIOPISTO BIOTIETEIDEN LAITOS PERINNÖLLISYYSTIEDE Kohdennettu uuden suku- polven DNA-sekvensointi aksonirappeumataudeissa: uudet KIF1A- ja HSPB1-mutaatiot ja fenotyypit Nella Junna 2015 Sisällysluettelo Lyhenteet ............................................................................................................................................. v 1. Johdanto ....................................................................................................................................... 1 2. Kirjallisuuskatsaus....................................................................................................................... 2 2.1 Hermosto ja neurologiset sairaudet ................................................................................... 2 2.2 Charcot-Marie-Toothin tauti 2 (CMT2) ........................................................................... 3 2.2.1 Oireet, hoidot ja ennuste .................................................................................................... 3 2.2.2 Sairauden aiheuttava mekanismi ....................................................................................... 4 2.2.3 CMT2:n jaottelu ja diagnosointi ........................................................................................ 4 2.3 CMT2:n genetiikka ............................................................................................................. 7 2.3.1 Molekyylimoottorit ja aksonaalinen kuljetus .................................................................... 7 2.3.2 Mitokondriodynamiikka .................................................................................................... 8 2.3.3 Sytoskeletonin toiminta ................................................................................................... 10 2.3.4 Muita funktioita ............................................................................................................... 11 2.4 Hereditäärinen spastinen paraplegia (HSP) ................................................................... 14 2.4.1 Oireet, hoidot ja ennuste .................................................................................................. 14 2.4.2 Sairauden aiheuttava mekanismi ..................................................................................... 15 2.4.3 HSP:n jaottelu ja diagnostiikka ....................................................................................... 15 2.5 HSP:n genetiikka ............................................................................................................... 16 2.5.1 Mitokondriodynamiikka .................................................................................................. 18 2.5.2 Aksonaalisen kuljetuksen häiriöt ..................................................................................... 18 2.5.3 ER-verkoston toiminta ..................................................................................................... 19 2.5.4 BMP-signalointi ............................................................................................................... 21 2.5.5 Endosomien Membraaniliikenne ..................................................................................... 23 2.5.6 Primaarinen myeliinihäiriö .............................................................................................. 23 2.5.7 Kortikospinaaliradan kehityshäiriöt................................................................................. 24 2.5.8 Lipidien synteesi ja metabolia ......................................................................................... 24 2.6 Kohdennettu uuden sukupolven sekvensointimenetelmä .............................................. 25 2.6.1 Uuden sukupolven sekvensointimenetelmät .................................................................... 25 2.6.2 Kohdennettu uuden sukupolven sekvensointimenetelmä ................................................ 26 ii 2.6.3 Sekvensointitulosten analysoiminen ................................................................................ 27 2.6.4 Kohdennetun NGS:n haasteet ja virhelähteet .................................................................. 28 2.6.5 Kohdennettu NGS diagnostiikan apuvälineenä ............................................................... 28 3. Tavoitteet .................................................................................................................................... 30 4. Materiaalit ja menetelmät .......................................................................................................... 31 4.1 Potilaat ................................................................................................................................ 31 4.1.1 CMT-potilaat ................................................................................................................... 31 4.1.2 HSP-potilaat ..................................................................................................................... 33 4.2 Kohdennettu uuden sukupolven sekvensointimenetelmä .............................................. 34 4.2.1 Sekvensointi ..................................................................................................................... 34 4.2.2 Geenipaneeli .................................................................................................................... 35 4.2.3 Ohjelmat ja tietokannat .................................................................................................... 36 4.2.4 Varianttien analysointi ..................................................................................................... 37 4.2.5 Pistemutaatiot .................................................................................................................. 38 4.2.6 Pienet insertiot ja deleetiot ............................................................................................... 39 4.3 Varianttien Sanger-sekvensointi ...................................................................................... 39 4.3.1 PCR-alukkeiden suunnittelu ............................................................................................ 39 4.3.2 PCR-ohjelmat .................................................................................................................. 40 4.3.3 Sekvensointi ..................................................................................................................... 43 4.4 Proteiinieristys fibroblasteista ja HSPB1 Western blot ................................................. 44 4.4.1 Fibroblastien kasvatus ja proteiinien eristys .................................................................... 44 4.4.2 Western blot ..................................................................................................................... 44 5. Tulokset ...................................................................................................................................... 46 5.1 Kohdennetun sekvensoinnin onnistuminen .................................................................... 46 5.2 Varianttien analysoinnin tulokset .................................................................................... 48 5.2.1 Varianttien analysointi ..................................................................................................... 48 5.2.2 Lopputulokset .................................................................................................................. 51 5.2.3 CMT-potilaiden lopputulokset ......................................................................................... 53 5.2.4 HSP-potilaiden lopputulokset .......................................................................................... 55 5.3 Western blot ....................................................................................................................... 56 iii 6. Tulosten tarkastelu .................................................................................................................... 57 6.1 Kohdennetun uuden sukupolven sekvensointimenetelmän onnistuminen .................. 57 6.1.1 Sekvensointi ..................................................................................................................... 57 6.1.2 Varianttien analysointi ..................................................................................................... 57 6.2 HSP- ja CMT-potilaiden molekulaarisen diagnoosin selvittäminen ............................ 59 6.2.1 Mutaatioiden patogeenisuuden arviointi .......................................................................... 59 6.2.1.1 Varmasti ja todennäköisesti patogeeniset mutaatiot ................................................ 60 6.2.1.2 Mahdolliset tautimutaatiot ........................................................................................ 63 6.2.1.3 Potilaat, joille ei löytynyt sairauden aiheuttanutta mutaatiota ................................. 64 6.2.2 Patogeenisten mutaatioiden tunnistamisen ongelmat ...................................................... 66 6.2.3 Kohdennetun NGS:n soveltuvuus diagnostiikassa .......................................................... 66 6.3 Jatkotutkimukset ............................................................................................................... 68 6.3.1 KIF1A-geenin de novo missense-mutaatiot moottoridomeenissa aiheuttavat vakavan taudinkuvan ................................................................................................................................
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