Unanswered Questions in the Genetic Basis of Primary Aldosteronism

Ute I. Scholl

doi:10.1055/s-0043-120066

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2017; 49(12): 963-968
DOI: 10.1055/s-0043-120066

Review

Unanswered Questions in the Genetic Basis of Primary Aldosteronism

Ute I. Scholl

¹Department of Nephrology, Medical School, Heinrich Heine University, University Hospital Düsseldorf, Düsseldorf, Germany

› Institutsangaben

Abstract

Over the past six years, the genetic basis of a significant fraction of primary aldosteronism (PA) cases has been solved. Breakthrough discoveries include the role of somatic variants in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes as causes of aldosterone-producing adenomas (APAs), and the recognition of three novel hyperaldosteronism syndromes with germline variants in the KCNJ5, CACNA1D, and CACNA1H genes. The description of somatic variants in CACNA1D and ATP1A1 in aldosterone-producing cell clusters (APCCs) suggests that these clusters are precursors of some aldosterone-producing adenomas. Yet, a number of questions remain unanswered. These include the genetic basis of about 40% of APAs without somatic variants in known genes. Do technical issues explain this finding, or are the unexplained APAs due to somatic copy number variation or rare variants in thus-far undiscovered genes? Similarly, the role of CTNNB1 (beta catenin) variants in APA pathogenesis is still unclear. The major question to be solved is the genetic basis of bilateral adrenal hyperplasia (BAH). Is BAH due to the bilateral occurrence of APCCs, to germline variants, or perhaps due to unknown serum factors? Lastly, the etiology of unsolved cases of apparently familial hyperaldosteronism remains to be discovered. It is expected that genetic studies over the next few years will lead to answers to at least some of the questions raised.

Key words

aldosterone-producing adenoma - bilateral adrenal hyperplasia - genetics - familial hyperaldosteronism

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References
1 Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA, Rabbia F, Veglio F, Mulatero P. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol 2017; 69: 1811-1820
2 Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300
3 Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J, Huete A, Gederlini A, Fardella CE. Primary aldosteronism and hypertensive disease. Hypertension 2003; 42: 161-165
4 Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young Jr. WF. The management of primary aldosteronism: case detection, diagnosis, and treatment: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016; 101: 1889-1916
5 Fernandes-Rosa FL, Giscos-Douriez I, Amar L, Gomez-Sanchez CE, Meatchi T, Boulkroun S, Zennaro MC. Different somatic mutations in multinodular adrenals with aldosterone-producing adenoma. Hypertension 2015; 66: 1014-1022
6 Iacobone M, Citton M, Viel G, Boetto R, Bonadio I, Tropea S, Mantero F, Rossi GP, Fassina A, Nitti D, Favia G. Unilateral adrenal hyperplasia: a novel cause of surgically correctable primary hyperaldosteronism. Surgery 2012; 152: 1248-1255
7 Seccia TM, Fassina A, Nussdorfer GG, Pessina AC, Rossi GP. Aldosterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course. Endocr Relat Cancer 2005; 12: 149-159
8 Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res 2015; 47: 941-946
9 Funder JW. Primary aldosteronism: New answers, new questions. Horm Metab Res 2015; 47: 935-940
10 DoD News Briefing. February 12, 2002; http://archive.defense.gov/Transcripts/Transcript.aspx?TranscriptID = 2636 . Accessed 09/03, 2017
11 Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768-772
12 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; jc20152149
13 Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension 2014; 64: 354-361
14 Spat A, Hunyady L. Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol Rev 2004; 84: 489-539
15 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
16 Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013; 45: 1055-1060
17 Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: 440-444
18 Tauber P, Aichinger B, Christ C, Stindl J, Rhayem Y, Beuschlein F, Warth R, Bandulik S. Cellular Pathophysiology of an Adrenal Adenoma-Associated Mutant of the Plasma Membrane Ca(2+)-ATPase ATP2B3. Endocrinology 2016; 157: 2489-2499
19 Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kucukkoylu S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol (Oxf) 2015; 83: 779-789
20 Akerstrom T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, Stalberg P, Robinson B, Alexander Iwen K, Dralle H, Walz MK, Lehnert H, Sidhu S, Gomez-Sanchez C, Hellman P, Bjorklund P. Activating mutations in CTNNB1 in aldosterone producing adenomas. Sci Rep 2016; 6: 19546
21 Wu VC, Wang SM, Chueh SJ, Yang SY, Huang KH, Lin YH, Wang JJ, Connolly R, Hu YH, Gomez-Sanchez CE, Peng KY, Wu KD. The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes. Sci Rep 2017; 7: 39121
22 Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, Liu CJ, Sanjanwala AR, Edwards MA, Gomez-Sanchez CE, Nanba K, Rainey WE. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A 2015; 112: E4591-E4599
23 Nishimoto K, Seki T, Kurihara I, Yokota K, Omura M, Nishikawa T, Shibata H, Kosaka T, Oya M, Suematsu M, Mukai K. Case report: Nodule development from subcapsular aldosterone-producing cell clusters causes hyperaldosteronism. J Clin Endocrinol Metab 2016; 101: 6-9
24 Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966; 95: 1109-1119
25 Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355: 262-265
26 Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A, Wang WH, Lifton RP. 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: 2533-2538
27 Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, Fischer E, Tizzani D, Pallauf A, Viola A, Amar L, Williams TA, Strom TM, Graf E, Bandulik S, Penton D, Plouin PF, Warth R, Allolio B, Jeunemaitre X, Veglio F, Reincke M. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 2012; 59: 235-240
28 Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC, Quack I, Rump LC, Thiel A, Lande M, Frazier BG, Rasoulpour M, Bowlin DL, Sethna CB, Trachtman H, Fahlke C, Lifton RP. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. eLife 2015; 4:
29 Nanba K, Chen AX, Omata K, Vinco M, Giordano TJ, Else T, Hammer GD, Tomlins SA, Rainey WE. Molecular heterogeneity in aldosterone-producing adenomas. J Clin Endocrinol Metab 2016; 101: 999-1007
30 Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O, Omeiri H, Rodriguez S, Perlemoine K, Rene-Corail F, Elarouci N, Sbiera S, Kroiss M, Allolio B, Waldmann J, Quinkler M, Mannelli M, Mantero F, Papathomas T, De Krijger R, Tabarin A, Kerlan V, Baudin E, Tissier F, Dousset B, Groussin L, Amar L, Clauser E, Bertagna X, Ragazzon B, Beuschlein F, Libe R, de Reynies A, Bertherat J. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 2014; 46: 607-612
31 Bonnet S, Gaujoux S, Launay P, Baudry C, Chokri I, Ragazzon B, Libe R, Rene-Corail F, Audebourg A, Vacher-Lavenu MC, Groussin L, Bertagna X, Dousset B, Bertherat J, Tissier F. Wnt/beta-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors. J Clin Endocrinol Metab 2011; 96: E419-E426
32 Goh G, Scholl UI, Healy JM, Choi M, Prasad ML, Nelson-Williams C, Kunstman JW, Korah R, Suttorp AC, Dietrich D, Haase M, Willenberg HS, Stalberg P, Hellman P, Akerstrom G, Bjorklund P, Carling T, Lifton RP. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 2014; 46: 613-617
33 Juhlin CC, Goh G, Healy JM, Fonseca AL, Scholl UI, Stenman A, Kunstman JW, Brown TC, Overton JD, Mane SM, Nelson-Williams C, Backdahl M, Suttorp AC, Haase M, Choi M, Schlessinger J, Rimm DL, Hoog A, Prasad ML, Korah R, Larsson C, Lifton RP, Carling T. Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma. J Clin Endocrinol Metab 2015; 100: E493-E502
34 Thiel A, Reis AC, Haase M, Goh G, Schott M, Willenberg HS, Scholl UI. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol 2015; 172: 677-685
35 Cao Y, He M, Gao Z, Peng Y, Li Y, Li L, Zhou W, Li X, Zhong X, Lei Y, Su T, Wang H, Jiang Y, Yang L, Wei W, Yang X, Jiang X, Liu L, He J, Ye J, Wei Q, Li Y, Wang W, Wang J, Ning G. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science 2014; 344: 913-917
36 Teo AE, Garg S, Haris Shaikh L, Zhou J, Karet Frankl FE, Gurnell M, Happerfield L, Marker A, Bienz M, Azizan EA, Brown MJ. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations. N Engl J Med 2015; 373: 1429-1436
37 Murtha TD, Carling T, Scholl UI. Pregnancy, Primary Aldosteronism, and Somatic CTNNB1 Mutations. N Engl J Med 2016; 374: 1492-1493
38 Azizan EA, Lam BY, Newhouse SJ, Zhou J, Kuc RE, Clarke J, Happerfield L, Marker A, Hoffman GJ, Brown MJ. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab 2012; 97: E819-E829
39 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: 319-322
40 Sukor N, Mulatero P, Gordon RD, So A, Duffy D, Bertello C, Kelemen L, Jeske Y, Veglio F, Stowasser M. 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: 1577-1582
41 Morimoto R, Satani N, Iwakura Y, Ono Y, Kudo M, Nezu M, Omata K, Tezuka Y, Seiji K, Ota H, Kawasaki Y, Ishidoya S, Nakamura Y, Arai Y, Takase K, Sasano H, Ito S, Satoh F. A case of bilateral aldosterone-producing adenomas differentiated by segmental adrenal venous sampling for bilateral adrenal sparing surgery. J Hum Hypertens 2016; 30: 379-385
42 Wu VC, Chueh SC, Chang HW, Lin WC, Liu KL, Li HY, Lin YH, Wu KD, Hsieh BS. Bilateral aldosterone-producing adenomas: differentiation from bilateral adrenal hyperplasia. QJM 2008; 101: 13-22
43 Li H, Yu X, Cicala MV, Mantero F, Benbrook A, Veitla V, Cunningham MW, Kem DC. Prevalence of angiotensin II type 1 receptor (AT1R)-activating autoantibodies in primary aldosteronism. J Am Soc Hypertens 2015; 9: 15-20
44 Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M, Deinum J, Beuschlein F, Kitamoto KK, Pham U, Morimoto R, Umakoshi H, Prejbisz A, Kocjan T, Naruse M, Stowasser M, Nishikawa T, Young Jr. WF, Gomez-Sanchez CE, Funder JW, Reincke M. Primary Aldosteronism Surgery Outcome i. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 2017; 5: 689-699
45 Palmiere C, Lesta Mdel M, Sabatasso S, Mangin P, Augsburger M, Sporkert F. Usefulness of postmortem biochemistry in forensic pathology: illustrative case reports. Leg Med (Tokyo) 2012; 14: 27-35
46 Parker RA. Distribution of the changes in the juxtaglomerular apparatus in human renal artery stenosis. Nephron 1967; 4: 315-325
47 Spyroglou A, Bozoglu T, Rawal R, De Leonardis F, Sterner C, Boulkroun S, Benecke AG, Monti L, Zennaro MC, Petersen AK, Doring A, Rossi A, Bidlingmaier M, Warth R, Gieger C, Reincke M, Beuschlein F. Diastrophic dysplasia sulfate transporter (SLC26A2) is expressed in the adrenal cortex and regulates aldosterone secretion. Hypertension 2014; 63: 1102-1109
48 Manichaikul A, Rich SS, Allison MA, Guagliardo NA, Bayliss DA, Carey RM, Barrett PQ. KCNK3 variants are associated with hyperaldosteronism and hypertension. Hypertension 2016; 68: 356-364