Pathogenesis of Familial Hyperaldosteronism Type II: New Concepts Involving Anion Channels

  • Michael StowasserEmail author
  • Martin Wolley
  • Aihua Wu
  • Richard D. Gordon
  • Julia Schewe
  • Gabriel Stölting
  • Ute I. Scholl
Hypertension and the Kidney (Robert M. Carey, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and the Kidney


Purpose of Review

The application of advanced genetic techniques has recently begun to unravel the genetic basis for familial primary aldosteronism type 2 (FH-II).

Recent Findings

Whole-exome sequencing in a large family with FH-II revealed a shared rare damaging heterozygous variant in CLCN2 (chr.3: g.184075850C>T, p.Arg172Gln) in three severely affected members. The gene encodes a chloride channel, ClC-2. A cohort of 80 unrelated individuals diagnosed with early-onset primary aldosteronism was also examined for CLCN2 mutations finding three further occurrences of p.Arg172Gln mutations and four single cases of other potentially damaging heterozygous mutations for an overall prevalence of 9.9%. A concurrent report also found a different CLCN2 mutation (p.Gly24Asp) in a single severely affected patient from a cohort of 12 with early-onset PA for a prevalence of 8.3%. Cases of primary aldosteronism associated with CLCN2 mutations appear to be bilateral and respond well to medical treatment. In the adrenal, ClC-2 has been demonstrated to localize predominantly to the zona glomerulosa (ZG), and functional analysis suggests that mutations in ClC-2 predispose ZG cells to depolarization, thus leading to calcium influx via activation of voltage-gated calcium channels and increased aldosterone production.


Germline CLCN2 mutations appear to account for a substantial proportion of early-onset primary aldosteronism cases, and genetic testing for mutations in this gene should be considered in appropriate cases.


Primary aldosteronism Familial hyperaldosteronism type II Genetics Chloride channel Anion channel Hypertension 



UIS is supported by grants from the Deutsche Forschungsgemeinschaft (SCHO 1386/2-1) and the Stiftung Charité (BIH Johanna Quandt Professorship). GS is supported by a grant from the Deutsche Forschungsgemeinschaft (STO 1260/1-1). AW is supported by a scholarship from the Commonwealth Government of Australia.

Compliance with Ethical Standards

Conflict of Interest

Heinrich Heine University Düsseldorf has filed a patent application: EP17209972, Diagnosis and Therapy of Primary Aldosteronism, with UIS as an inventor. Other authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966;95(22):1109–19 This was the first description of familial PA (FH-I). PubMedPubMedCentralGoogle Scholar
  2. 2.
    •• Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355(6357):262–5. This was the first report of a genetic mutation causing familial PA (FH-I). CrossRefPubMedGoogle Scholar
  3. 3.
    Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 1992;2(1):66–74. Scholar
  4. 4.
    •• Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768–72. This paper was first to descibe somatic mutations in KCNJ5 within aldosterone-producing adenomas and inherited KCNJ5 mutations in genomic DNA causing familial PA (FH-III). CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A. 2012;109(7):2533–8. Scholar
  6. 6.
    Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012;59(2):235–40. Scholar
  7. 7.
    •• Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. elife. 2015;4. This paper first reported genomic CACNA1H mutations as the basis of early onset (including familial) PA (FH-IV).
  8. 8.
    Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, et al. CACNA1H mutations are associated with different forms of primary Aldosteronism. EBioMedicine. 2016;13:225–36. Scholar
  9. 9.
    •• Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013;45(9):1050–4. This paper reported somatic mutations in CACNA1D within aldosterone-producing adenomas and inherited CACNA1D mutations in genomic DNA causing early onset PA. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    • Fernandes-Rosa FL, Daniil G, Orozco IJ, Goppner C, El Zein R, Jain V, et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet. 2018;50(3):355–61. This case report described a patient with early onset PA due to a CLCN2 mutation. CrossRefPubMedGoogle Scholar
  11. 11.
    •• Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018;50(3):349–54. This paper described inherited mutations in CLCN2 as the cause of PA in a large Australian familiy with FH-II and in seven other unrelated probands (one with two other affected family members) with early onset PA and showed that these mutations lead to gain of function, causing zona glomerulosa cell membrane depolarization, and enhanced expression of CYP11B2 (encoding aldosterone synthase). CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45(1):3–17.PubMedGoogle Scholar
  13. 13.
    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The Management of Primary Aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889–916. Scholar
  14. 14.
    • Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol. 1994;21(4):315–8 A landmark study drawing attention to the previously unrecognized high prevalence of PA amongst normokalemic hypertensive patients attending a tertiary referral centre. CrossRefGoogle Scholar
  15. 15.
    Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48(11):2293–300. Scholar
  16. 16.
    Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J, et al. Primary aldosteronism and hypertensive disease. Hypertension. 2003;42(2):161–5. Scholar
  17. 17.
    Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40(6):892–6.CrossRefGoogle Scholar
  18. 18.
    Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, et al. Prevalence and clinical manifestations of primary Aldosteronism encountered in primary care practice. J Am Coll Cardiol. 2017;69(14):1811–20. Scholar
  19. 19.
    Hamlet SM, Tunny TJ, Woodland E, Gordon RD. Is aldosterone/renin ratio useful to screen a hypertensive population for primary aldosteronism? Clin Exp Pharmacol Physiol. 1985;12(3):249–52.CrossRefPubMedGoogle Scholar
  20. 20.
    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89(3):1045–50. Scholar
  21. 21.
    Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45(8):1243–8. Scholar
  22. 22.
    Monticone S, D'Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6(1):41–50. Scholar
  23. 23.
    Stowasser M, Sharman J, Leano R, Gordon RD, Ward G, Cowley D, et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab. 2005;90(9):5070–6. Scholar
  24. 24.
    Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168(1):80–5. Scholar
  25. 25.
    Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018;6(1):51–9. Scholar
  26. 26.
    Stowasser M, Bachmann AW, Jonsson JR, Tunny TJ, Klemm SA, Gordon RD. Clinical, biochemical and genetic approaches to the detection of familial hyperaldosteronism type I. J Hypertens. 1995;13(12 Pt 2):1610–3.PubMedGoogle Scholar
  27. 27.
    •• Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharmacol Physiol. 1992;19(5):319–22 This was the first paper to coin the term “FH-II”. CrossRefPubMedGoogle Scholar
  28. 28.
    •• Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol. 1991;18(5):283–6 This was the first paper to describe a group of families with non-glucocorticoid-suppressible PA. CrossRefPubMedGoogle Scholar
  29. 29.
    Stowasser M, Gordon RD. Primary aldosteronism: learning from the study of familial varieties. J Hypertens. 2000;18(9):1165–76.CrossRefPubMedGoogle Scholar
  30. 30.
    Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res. 2015;47(13):941–6. Scholar
  31. 31.
    Scholl UI. Unanswered questions in the genetic basis of primary aldosteronism. Horm Metab Res. 2017;49(12):963–8. Scholar
  32. 32.
    Carss KJ, Stowasser M, Gordon RD, O'Shaughnessy KM. Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II. J Hum Hypertens. 2011;25(9):560–4. Scholar
  33. 33.
    So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, New MI, et al. Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity. J Hypertens. 2005;23(8):1477–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Sukor N, Mulatero P, Gordon RD, So A, Duffy D, Bertello C, et al. Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families. J Hypertens. 2008;26(8):1577–82. Scholar
  35. 35.
    Torpy DJ, Gordon RD, Lin JP, Huggard PR, Taymans SE, Stowasser M, et al. Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene. J Clin Endocrinol Metab. 1998;83(9):3214–8. CrossRefPubMedGoogle Scholar
  36. 36.
    Torpy DJ, Stratakis CA, Gordon RD. Linkage analysis of familial hyperaldosteronism type II--absence of linkage to the gene encoding the angiotensin II receptor type 1. J Clin Endocrinol Metab. 1998;83(3):1046. Scholar
  37. 37.
    Jeske YW, So A, Kelemen L, Sukor N, Willys C, Bulmer B, et al. Examination of chromosome 7p22 candidate genes RBaK, PMS2 and GNA12 in familial hyperaldosteronism type II. Clin Exp Pharmacol Physiol. 2008;35(4):380–5. Scholar
  38. 38.
    Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93(8):3117–23. Scholar
  39. 39.
    Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2008;93(8):2972–4. Scholar
  40. 40.
    Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE. Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. Endocrinology. 2012;153(4):1774–82. Scholar
  41. 41.
    Hu C, Rusin CG, Tan Z, Guagliardo NA, Barrett PQ. Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators. J Clin Invest. 2012;122(6):2046–53. Scholar
  42. 42.
    Reimer EN, Walenda G, Seidel E, Scholl UI. CACNA1H mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by Mibefradil. Endocrinology. 2016;157:3016–22. Scholar
  43. 43.
    Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, et al. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension. 2014;64(2):354–61. Scholar
  44. 44.
    Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A meta-analysis of somatic KCNJ5 K channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab. 2015;100:E1089–95. Scholar
  45. 45.
    Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45(9):1055–60. Scholar
  46. 46.
    • Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45(4):440–4. This paper described the occurrence of somatic ATP1A1 and ATP2B3 mutations in aldosterone-producing adenomas. CrossRefPubMedGoogle Scholar
  47. 47.
    Nanba K, Omata K, Else T, Beck PCC, Nanba AT, Turcu AF, et al. Targeted molecular characterization of aldosterone-producing adenomas in white Americans. J Clin Endocrinol Metab. 2018;103(10):3869–76. Scholar
  48. 48.
    Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A. 2015;112(33):E4591–9. Scholar
  49. 49.
    Omata K, Satoh F, Morimoto R, Ito S, Yamazaki Y, Nakamura Y, et al. Cellular and genetic causes of idiopathic hyperaldosteronism. Hypertension. 2018;72(4):874–80. Scholar
  50. 50.
    Thiemann A, Grunder S, Pusch M, Jentsch TJ. A chloride channel widely expressed in epithelial and non-epithelial cells. Nature. 1992;356(6364):57–60. Scholar
  51. 51.
    Zuniga L, Niemeyer MI, Varela D, Catalan M, Cid LP, Sepulveda FV. The voltage-dependent ClC-2 chloride channel has a dual gating mechanism. J Physiol. 2004;555(Pt 3):671–82. Scholar
  52. 52.
    Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014;15(10):637–54. Scholar
  53. 53.
    Stolting G, Teodorescu G, Begemann B, Schubert J, Nabbout R, Toliat MR, et al. Regulation of ClC-2 gating by intracellular ATP. Pflugers Arch. 2013;465(10):1423–37. Scholar
  54. 54.
    Feng L, Campbell EB, Hsiung Y, MacKinnon R. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science. 2010;330(6004):635–41. Scholar
  55. 55.
    Grunder S, Thiemann A, Pusch M, Jentsch TJ. Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume. Nature. 1992;360(6406):759–62. Scholar
  56. 56.
    Varela D, Niemeyer MI, Cid LP, Sepulveda FV. Effect of an N-terminus deletion on voltage-dependent gating of the ClC-2 chloride channel. J Physiol. 2002;544(Pt 2):363–72.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Jordt SE, Jentsch TJ. Molecular dissection of gating in the ClC-2 chloride channel. EMBO J. 1997;16(7):1582–92. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Spat A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004;84(2):489–539. Scholar
  59. 59.
    Chorvatova A, Gendron L, Bilodeau L, Gallo-Payet N, Payet MD. A Ras-dependent chloride current activated by adrenocorticotropin in rat adrenal zona glomerulosa cells. Endocrinology. 2000;141(2):684–92. Scholar
  60. 60.
    Maniero C, Zhou J, Shaikh LH, Azizan EA, McFarlane I, Neogi S, et al. Role of ANO4 in regulation of aldosterone secretion in the zona glomerulosa of the human adrenal gland. Lancet. 2015;385(Suppl 1):S62. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Michael Stowasser
    • 1
    Email author
  • Martin Wolley
    • 1
  • Aihua Wu
    • 1
  • Richard D. Gordon
    • 1
  • Julia Schewe
    • 2
  • Gabriel Stölting
    • 2
  • Ute I. Scholl
    • 2
  1. 1.Endocrine Hypertension Research CentreUniversity of Queensland Diamantina Institute, Princess Alexandra HospitalBrisbaneAustralia
  2. 2.Department of Nephrology and Medical Intensive Care, BCRTCharité – Universitätsmedizin Berlin and Berlin Institute of HealthBerlinGermany

Personalised recommendations