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CLCN2 Clicks with Aldosterone-Producing Adenomas, Too! 5 181 U I Scholl CLCN2 in aldosterone-producing 181:5 C21–C22 Commentary adenomas CLCN2 clicks with aldosterone-producing adenomas, too! Ute I Scholl1,2,3 1Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin Berlin, Corporate Member of Correspondence Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany, 2Berlin should be addressed Institute of Health (BIH), Berlin, Germany, and 3Charité — Universitätsmedizin Berlin, BCRT - BIH Center for to U I Scholl Regenerative Therapies, Berlin, Germany Email [email protected] Abstract Germline mutations in the chloride channel gene CLCN2 have been described as cause of familial hyperaldosteronism type II. In this issue, Dutta and colleagues in a groundbreaking study identify a somatic (tumor-specific)CLCN2 mutation in an aldosterone-producing adenoma, expanding the disease spectrum associated with CLCN2 mutations. European Journal of Endocrinology (2019) 181, C21–C22 In primary aldosteronism, inappropriately elevated (encoding for another calcium channel), have so far aldosterone levels cause hypertension and – as an only been identified in familial hyperaldosteronism 5( ), optional finding – hypokalemia. Contrary to historic raising the question whether do not provide sufficient estimates, primary aldosteronism is now considered the proliferative stimulus for adenoma formation. commonest cause of secondary hypertension, present Most recently, two groups reported germline mutations European Journal of Endocrinology in >5% of hypertensive patients. Patients with primary in the CLCN2 gene in familial hyperaldosteronism. aldosteronism typically either have an aldosterone- The report by Scholl et al. described mutations in eight producing adenoma (a benign tumor of the adrenal families (two de novo, 17 individuals total with CLCN2 cortex) or bilateral adrenal hyperplasia. Rarely, familial mutations) (6) and dubbed the associated syndrome aggregation is observed (‘familial hyperaldosteronism’) (1). familial hyperaldosteronism type II; the study by Genetic studies over the last decade have provided insight Fernandes-Rosa et al. identified onede novo case (7). into the molecular pathogenesis of primary aldosteronism, CLCN2 encodes for the voltage-gated chloride channel identifying new somatic (tumor-specific) mutations in ClC-2, the first anion channel implicated in primary aldosterone-producing adenomas and germline (inherited aldosteronism and hypertension. In both studies, or de novo) mutations in familial hyperaldosteronism. electrophysiology demonstrated that ClC-2 mutations The two genes that are most frequently mutated in in familial hyperaldosteronism cause increased chloride aldosterone-producing adenomas are KCNJ5, encoding permeability. The ensuing cellular depolarization leads for a potassium channel, and CACNA1D, encoding for a to activation of voltage-gated calcium channels, influx of calcium channel. Interestingly, germline mutations in the calcium and increased aldosterone production. same genes can also cause Mendelian forms of primary In a landmark paper in this issue of the European aldosteronism (2, 3). Contrary, mutations in some genes, Journal of Endocrinology, Dutta et al. add an important piece such as ATP1A1 and ATP2B3 encoding ATPases (4), are of the primary aldosteronism genetics puzzle. They Sanger only found in aldosterone-producing adenomas, but not sequenced the CLCN2 coding regions in 80 aldosterone- in familial hyperaldosteronism, likely because germline producing adenomas from Norway, Sweden and Germany mutations would be lethal. Mutations in other genes, (8). One of these tumors carried a somatic CLCN2 mutation. namely CYP11B2 (aldosterone synthase) and CACNA1H Remarkably, this somatic mutation (p.Gly24Asp) was https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0688 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:57:29PM via free access -19-0688 Commentary U I Scholl CLCN2 in aldosterone-producing 181:5 C22 adenomas identical with the de novo germline mutation reported in the mutations in aldosterone-producing adenomas (2, 3). patient described by Fernandes-Rosa et al. (7). The tumor Dutta et al. turn the story around, expanding the disease with CLCN2 mutation was 13 mm in size (thus, rather spectrum associated with gain-of-function mutations in small) and was found in a 35-year-old man with elevated CLCN2 from familial hyperaldosteronism to aldosterone- aldosterone levels. Preoperative adrenal venous sampling producing adenomas. demonstrated lateralization of aldosterone production. After surgical tumor removal, both blood pressure and aldosterone:renin ratio normalized. RNA expression levels Declaration of interest Rockefeller University has filed a patent application (PCT/US2018/033362, of CYP11B2 (aldosterone synthase) in the tumor were Compositions and methods for diagnosing and treating diseases and high, providing further evidence that the lesion was the disorders associated with mutant KCNJ5), with UIS as one of the inventors. cause of the patient’s primary aldosteronism. The p.Gly24Asp mutation changes a conserved residue in the N-terminus of the ClC-2 channel. Its impact on Funding This work was supported by grants from the Stiftung Charité (BIH Johanna channel function and aldosterone production has been Quandt Professorship) and the Deutsche Forschungsgemeinschaft (DFG, well studied in vitro. Mutant channels show higher current SCHO 1386/2-1). amplitudes and altered voltage-dependent gating. In a cellular model of glomerulosa function, transfection of channels carrying the mutation significantly raises References aldosterone production compared to wildtype channels (7). 1 Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M & Young WF, Jr. The management of Collectively, there is no doubt that the somatic CLCN2 primary aldosteronism: case detection, diagnosis, and treatment: mutation reported by Dutta et al. accounts for increased an Endocrine Society clinical practice guideline. Journal of Clinical aldosterone production in the tumor. Some open Endocrinology and Metabolism 2016 101 1889–1916. (https://doi. org/10.1210/jc.2015-4061) questions remain: Do CLCN2 mutations cause sufficient 2 Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, proliferation to cause tumor formation (as mentioned, Ji W, Cho Y, Patel A, Men CJ et al. K+ channel mutations in the tumor reported by Dutta et al. was quite small) or do adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011 331 768–772. (https://doi.org/10.1126/ tumors with CLCN2 mutations carry additional somatic science.1198785) mutations that account for proliferation? How frequent 3 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, are somatic CLCN2 mutations in aldosterone-producing Fonseca AL, Korah R, Starker LF, Kunstman JW et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone- adenomas? Are CYP11B2 or CACNA1H mutations also producing adenomas and primary aldosteronism. Nature Genetics European Journal of Endocrinology rare causes of aldosterone-producing adenomas? What 2013 45 1050–1054. (https://doi.org/10.1038/ng.2695) is the phenotype associated with CLCN2 mutations 4 Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E et al. (e.g. tumors with KCNJ5 mutations are typically large Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone- and associated with female gender)? Exome sequencing producing adenomas and secondary hypertension. Nature Genetics of the tumor with CLCN2 mutation and normal tissue, 2013 45 440–444, 444e1. (https://doi.org/10.1038/ng.2550) 5 Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, as well as targeted sequencing of large cohorts could Loring E, Prasad ML, Goh G, Carling T, Juhlin CC et al. Recurrent provide additional insights. In any case, the study by gain of function mutation in calcium channel CACNA1H causes Dutta et al. is a milestone toward the identification early-onset hypertension with primary aldosteronism. ELife 2015 4 e06315. (https://doi.org/10.7554/eLife.06315) of additional rare somatic mutations in aldosterone- 6 Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, producing adenomas, further emphasizing the long- Vichot AA, Jin SC, Loring E, Untiet V et al. CLCN2 chloride channel neglected role of anion channels in zona glomerulosa mutations in familial hyperaldosteronism type II. Nature Genetics 2018 50 349–354. (https://doi.org/10.1038/s41588-018-0048-5) function and primary aldosteronism. Lastly, it provides 7 Fernandes-Rosa FL, Daniil G, Orozco IJ, Goppner C, El Zein R, Jain V, yet another example of the fruitful interactions between Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H et al. A gain-of- the studies of rare Mendelian diseases (such as familial function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nature Genetics 2018 50 355–361. (https:// hyperaldosteronism) and more common sporadic doi.org/10.1038/s41588-018-0053-8) disorders (such as aldosterone-producing adenomas): 8 Dutta RK, Arnesen T, Heie A, Walz M, Alesina P, Söderkvist P & The identification of germline mutations in the KCNJ5 Gimm O. Case report: a somatic mutation in CLCN2 identified in a sporadic aldosterone producing adenoma. European Journal of and the CACNA1D genes in familial hyperaldosteronism Endocrinology 2019 181 K37–K41. (https://doi.org/10.1530/EJE-19- was inspired by the discovery of corresponding somatic 0377) Received 26 August 2019 Accepted 6 September 2019 https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 09:57:29PM via free access.
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