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

  • Hypertension and the Kidney (Robert M. Carey, Section Editor)
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Abstract

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.

Summary

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.

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References

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

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/355262a0 This was the first report of a genetic mutation causing familial PA (FH-I).

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ng0992-66.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1198785 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1121407109.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1161/HYPERTENSIONAHA.111.183996.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.7554/eLife.06315 This paper first reported genomic CACNA1H mutations as the basis of early onset (including familial) PA (FH-IV).

  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. https://doi.org/10.1016/j.ebiom.2016.10.002.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/ng.2695 This paper reported somatic mutations in CACNA1D within aldosterone-producing adenomas and inherited CACNA1D mutations in genomic DNA causing early onset PA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/s41588-018-0053-8 This case report described a patient with early onset PA due to a CLCN2 mutation.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/s41588-018-0048-5 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45(1):3–17.

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2015-4061.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jacc.2006.07.059.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1161/01.HYP.0000079505.25750.11.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jacc.2017.01.052.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2003-031337.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jacc.2005.01.015.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S2213-8587(17)30319-4.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2005-0681.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1001/archinternmed.2007.33.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S2213-8587(17)30367-4.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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”.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  29. Stowasser M, Gordon RD. Primary aldosteronism: learning from the study of familial varieties. J Hypertens. 2000;18(9):1165–76.

    Article  CAS  PubMed  Google Scholar 

  30. Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res. 2015;47(13):941–6. https://doi.org/10.1055/s-0035-1564166.

    Article  CAS  PubMed  Google Scholar 

  31. Scholl UI. Unanswered questions in the genetic basis of primary aldosteronism. Horm Metab Res. 2017;49(12):963–8. https://doi.org/10.1055/s-0043-120066.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/jhh.2010.93.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1097/HJH.0b013e3283028352.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jcem.83.9.5086.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jcem.83.3.4668-10.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1440-1681.2008.04882.x.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2008-0594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2008;93(8):2972–4. https://doi.org/10.1210/jc.2008-1241.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/en.2011-1733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1172/JCI61996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1210/en.2016-1170.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1161/HYPERTENSIONAHA.114.03419.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2015-2149.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ng.2716.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ng.2550 This paper described the occurrence of somatic ATP1A1 and ATP2B3 mutations in aldosterone-producing adenomas.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/jc.2018-01004.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.1505529112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1161/HYPERTENSIONAHA.118.11086.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/356057a0.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1113/jphysiol.2003.060046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/nrn3819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00424-013-1286-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1126/science.1195230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/360759a0.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jordt SE, Jentsch TJ. Molecular dissection of gating in the ClC-2 chloride channel. EMBO J. 1997;16(7):1582–92. https://doi.org/10.1093/emboj/16.7.1582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Spat A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004;84(2):489–539. https://doi.org/10.1152/physrev.00030.2003.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/endo.141.2.7328.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0140-6736(15)60377-4.

    Article  PubMed  Google Scholar 

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Funding

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.

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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.

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Stowasser, M., Wolley, M., Wu, A. et al. Pathogenesis of Familial Hyperaldosteronism Type II: New Concepts Involving Anion Channels. Curr Hypertens Rep 21, 31 (2019). https://doi.org/10.1007/s11906-019-0934-y

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