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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 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 ), 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 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 , 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

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-19-0688 European Journal of Endocrinology https://eje.bioscientifica.com was inspired by the discovery ofcorrespondingsomatic was inspiredbythediscovery and the The identificationofgermline mutationsinthe disorders (suchasaldosterone-producingadenomas): hyperaldosteronism) andmorecommonsporadic the studiesofrareMendeliandiseases(suchasfamilial yet anotherexampleofthefruitfulinteractionsbetween aldosteronism. Lastly,function and primary itprovides neglected roleofanionchannelsinzonaglomerulosa producing adenomas,furtheremphasizingthelong- of additional rare somatic mutations in aldosterone- Dutta provide additional insights. In any case, the study by as well as targeted sequencing of large cohorts could of the tumor with and associated with femalegender)? Exome sequencing (e.g. tumorswith is thephenotypeassociatedwith rare causesofaldosterone-producingadenomas?What adenomas? Are are somatic mutations that account forproliferation? How frequent tumors with wasquitesmall)ordo the tumorreportedbyDutta et al. proliferation tocausetumorformation(asmentioned, questions remain: Do aldosterone productioninthetumor. Someopen mutation reportedbyDutta aldosterone productioncomparedtowildtypechannels( the mutation significantly raises of channels carrying a cellularmodelofglomerulosafunction,transfection amplitudes andalteredvoltage-dependentgating.In well studied channel functionandaldosteroneproductionhasbeen in theN-terminusofClC-2channel.Itsimpacton cause ofthepatient’s aldosteronism. primary high, providingfurtherevidencethatthelesionwas of aldosterone:renin rationormalized.RNAexpressionlevels After surgical tumor removal, both blood pressure and demonstrated lateralizationofaldosteroneproduction. aldosterone levels.Preoperativeadrenalvenoussampling small) andwasfoundina35-year-oldmanwithelevated with patient describedby Fernandes-Rosa identical withthe Commentary CYP11B2 Collectively, thereisnodoubtthatthesomatic residue The p.Gly24Asp mutation changes a conserved CLCN2 t al. et CACNA1D (aldosterone synthase) in the tumor were (aldosteronesynthase)inthetumorwere in vitro is a milestone toward the identification CLCN2 mutationwas13 CLCN2 CYP11B2 de novo . Mutant channels show higher current . Mutantchannelsshowhighercurrent genesinfamilial hyperaldosteronism KCNJ5 mutationsinaldosterone-producing CLCN2 mutations carry additionalsomatic mutationscarry CLCN2 germline mutation reported in the germlinemutationreportedinthe or mutationsaretypicallylarge mutation and normal tissue, et al. mutationscause sufficient CACNA1H mm in size (thus, rather mm insize(thus,rather U IScholl accountsforincreased et al. CLCN2 mutations also ( 7 ). The tumor ). Thetumor mutations KCNJ5 CLCN2 7 ).

Accepted 6September2019 Received 26August2019 References SCHO 1386/2-1). (DFG, Forschungsgemeinschaft Deutsche the and Professorship) Quandt Johanna (BIH Charité Stiftung the from grants by supported was work This Funding and diseases treating and disorders associatedwithmutant diagnosing for methods and Compositions (PCT/US2018/033362, application patent a filed has University Rockefeller Declaration ofinterest producing adenomas. CLCN2 spectrum associatedwithgain-of-functionmutationsin Dutta mutations inaldosterone-producingadenomas(

adenomas CLCN2 inaldosterone-producing 2 1 7 6 5 4 3 8 Funder JW, Carey RM,Mantero F, Murad MH,Reincke M, Dutta RK,Arnesen T, Heie A,Walz M, Alesina P, Söderkvist P& Fernandes-Rosa FL, Daniil G,Orozco IJ,Goppner C,ElZein R,Jain V, Scholl UI, Stolting G,Schewe J,Thiel A,Tan H, Nelson-Williams C, Scholl UI, Stolting G,Nelson-Williams C, Vichot AA, Choi M, Beuschlein F, Boulkroun S,Osswald A,Wieland T, Nielsen HN, Scholl UI, Goh G,Stolting G,deOliveira RC,Choi M,Overton JD, Choi M, Scholl UI,Yue P, Bjorklund P, Zhao B,Nelson-Williams C, Shibata H, Stowasser M&Young WF, Jr. Themanagementof 2013 Endocrinology andMetabolism an EndocrineSocietyclinicalpracticeguideline. aldosteronism:casedetection,diagnosis,andtreatment: primary 0377 Endocrinology in asporadicaldosteroneproducingadenoma. Gimm O. Casereport:asomaticmutation inCLCN2identified doi.org/10.1038/s41588-018-0053-8) aldosteronism. primary function mutationintheCLCN2chloridechannelgenecauses Boulkroun S, Jeunemaitre X,Amar L,Lefebvre H 2018 mutations infamilialhyperaldosteronismtypeII. Vichot AA, Jin SC,Loring E,Untiet V e06315. aldosteronism. early-onset hypertensionwithprimary gain offunctionmutationincalciumchannelCACNA1Hcauses Loring E, Prasad ML,Goh G,Carling T, Juhlin CC hypertension. producing adenomasandsecondary Somatic mutationsinATP1A1 andATP2B3 leadtoaldosterone- Lichtenauer UD, Penton D,Schack VR,Amar L,Fischer E 2013 aldosteronism. producing adenomasandprimary germline CACNA1Dcalciumchannelmutationsinaldosterone- Fonseca AL, Korah R,Starker LF, Kunstman JW science.1198785) hypertension. adrenal aldosterone-producingadenomasandhereditary Ji W, Cho Y, Patel A,Men CJ org/10.1210/jc.2015-4061) et al. fromfamilialhyperaldosteronismtoaldosterone- ) 50 45 45 349–354. 440–444,444e1. 1050–1054. (https://doi.org/10.7554/eLife.06315) turn the story around,expandingthedisease turnthestory 2019 Science 181 (https://doi.org/10.1038/s41588-018-0048-5) (https://doi.org/10.1038/ng.2695) 2011 K37–K41. Nature Genetics (https://doi.org/10.1038/ng.2550) Downloaded fromBioscientifica.com at09/30/202109:57:29PM 331 2016 et al. KCNJ5 768–772. ( https://doi.org/10.1530/EJE-19- K+channelmutationsin 101 ), withUISasoneoftheinventors. et al 2018 1889–1916. . CLCN2chloridechannel (https://doi.org/10.1126/ 181 50 European Journal of of European Journal et al :5 355–361. Journal ofClinical Journal et al Nature Genetics Nature Genetics et al . Somaticand Nature Genetics (https://doi. . Again-of- . Recurrent ELife et al (https:// 2015 . 2 C22 ,

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