Somatic Mutations in Primary Aldosteronism - The Most Common Cause for Secondary Hypertension

Authors

  • Siti Khadijah Syed Mohammed Nazri Department of Medicine, The National University of Malaysia (UKM) Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia. Author
  • Elena Azizan Department of Medicine, The National University of Malaysia (UKM) Medical Centre, 56000 Cheras, Kuala Lumpur, Malaysia Author

Keywords:

Primary Aldosteronism, hypertension, hyperaldosteronism, mutation

Abstract

Hypertension is highly prevalent in Malaysia and even the rest of the world. Primary aldosteronism (PA) is one of the most common treatable cause of secondary hypertension.  PA commonly occurs due to a unilateral aldosterone-producing adenoma (APA) or due to bilateral adrenal hyperplasia. Up to one in five resistant hypertension cases are due to PA. Therefore, there are a high number of individuals who have the potential to be cured of their hypertension. In the past decade, five genes have been found to cause excess aldosterone production in APAs which are KCNJ5ATP1A1ATP2B3CACNA1D and CTNNB1. These somatic mutations have been found to activate the intracellular signalling pathway that regulates aldosterone production. Herein, we review the genetic causes of PA as a result of aldosterone-stimulating somatic mutations, the expression profile of the aldosterone-driver gene, and the associated mechanism of actions.

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References

Akerstrom, T., Crona, J., Delgado Verdugo, A., Starker, L. F., Cupisti, K., Willenberg, H. S., Knoefel, W. T., Saeger, W., Feller, A., Ip, J., Soon, P., Anlauf, M., Alesina, P.F., Schmid, K. W., Decaussin, M., Levillain, P., Wängberg, B., Peix, J-L., Robinson, B., Zedenius, J., Bäckdahl, M., Caramuta, S., Iwen, K.A., Botling, J., Stålberg, P., Kraimps, J-L., Dralle, H., Hellman, P., Sidhu, S., Westin, G., Lehnert, H., Walz, M.K., Åkerström, G., Carling, T., Choi, M., Lifton, R.P. & Björklund, P. 2012. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 7: e41926.

Akerstrom, T., Willenberg, H. S., Cupisti, K., Ip, J., Backman, S., Moser, A., Maharjan, R., Robinson, B., Iwen, K. A., Dralle, H., Volpe, C.D., Backdahl, M., Botling, J., Stalberg, P., Westin, G., Walz, M.K., Lehnert, H., Sidhu, S., Zedenius, J., Bjorklund, P. & Hellman, P. 2015. Novel somatic mutations and distinct molecular signature in aldosterone producing adenomas. Endocrine-Related Cancer 22:735-744.

Angers, S. & Moon, R.T. 2009. Proximal events in Wnt signal transduction. Nature Reviews Molecular Cell Biology 10:468–477.

Azizan, Elena AB, Lam, B.Y. H., Newhouse, S. J., Zhou, J., Kuc, R. E., Clarke, J., Happerfield, L., Marker, A., Hoffman, G.J. & Brown, M.J. 2012. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa-and zona fasciculata-like tumors. The Journal of Clinical Endocrinology 97 5: E819-E829.

Azizan, E. A., Poulsen, H., Tuluc, P., Zhou, J., Clausen, M.V., Lieb, A., Maniero, C., Garg, S., Bochukova, E.G., Zhao, W., Shaikh, L.H., Brighton, C.A., Teo, A.E.D., Davenport, A.P., Dekkers, T., Tops, B., Küsters, B., Ceral, J., Yeo, G.S.H., Neogi, S.G., McFarlane, I., Rosenfeld, N., Marass, F., Hadfield, J., Margas,W., Chaggar, K., Solar, M., Deinum, J., Dolphin, A.C., Farooqi, I.S., Striessnig, J., Nissen, P. & Brown, M.J. 2013. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nature Genetics 45:1055–1060.

Beuschlein, F., Boulkroun, S., Osswald, A., Wieland, T., Nielsen, H. N., Lichtenauer, U. D., Penton, D., Schack, V.R., 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,P-F., Mantero, F., Meitinger, T., Mulatero, P., Jeunemaitre, X., Warth, R.,Vilsen, B., Zennaro, M-C., Strom, T.M. & Reincke, M. 2013. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nature Genetics 45(4):440–444, 444e1–2.

Bjorklund, P., Lindberg, D., Akerstrom, G. & Westin, G. 2008. Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients. Molecular Cancer 7:53.

Boulkroun, S., Samson-Couterie, B., Golib-Dzib, J-F., Amar, L., Plouin, P-F., Sibony, M.,Lefebvre, H., Louiset, E., Jeunemaitre, X., Meatchi, T., Benecke, A., Lalli, E. & Zennaro, M-C. 2011. Aldosterone-producing adenoma formation in the adrenal cortex involves expression of stem/progenitor cell markers. Endocrinology 152: 4753–4763.

Cali, T., Lopreiato, R., Shimony, J., Vineyard, M., Frizzarin, M., Zanni, G., Zanotti, G., Brini, M., Shinawi, M. & Carafoli, E. 2015. A novel mutation in isoform 3 of the plasma membrane Ca2+ pump impairs cellular Ca2+ homeostasis in a patient with cerebellar ataxia and laminin subunit 1 mutations. Journal of Biological Chemistry 290:16132 16141.

Catterall, W.A. 2011. Voltage-gated calcium channels. Cold Spring Harbor Perspectives in Biology 3 a003947.

Cheng, C.J., Sung C.C., Wu, S.T., Lin, Y.C., Sytwu, H.K., Huang, C.L. & Lin S.H. 2015. Novel KCNJ5 mutations in sporadic aldosterone -producing adenoma reduce Kir3.4 membrane abundance. J Clin Endocrinol Metab 100(1): E155-E163.

Choi, M., Scholl UI, Yue P, Björklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C.J., Lolis, E., Wisgerhof, M. V., Geller, D.S., Mane, S., Hellman, P., Westin, G., Åkerström, G., Wang, W., Carling, T., Lifton, R.P. 2011. K+ channel mutations in adrenal aldosterone-producing adenonomas and hereditary hypertension. Science 331(6018):768–772.

Conn, J. W. 1966. The evolution of primary aldosteronism: 1954–1967. Harvey Lecture 62: 257–291.

Czogalla, J., Vohra, T., Penton, D., Kirschmann, M., Craigie, E. & Loffing, J. 2016. The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion. Pflugers Archiv 468: 849–858.

Durand, J., Lampron, A., Mazzuco, T. L., Chapman, A. & Bourdeau, I. 2011. Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations. The Journal of clinical endocrinology and metabolism 96: E1206–1211.

Dutta, K.R., Welander, J., Brauckhoff, M., Walz, M., Alesina, P., Arnesen, T., Söderkvist, P., & Gimm, O. 2013.Complementary somatic mutations KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas. Endocr Relat Cancer 21(1): L1–L4.

Dutta, K. R., Söderkvist, P. & Gimm, O. 2016. Genetics of Primary Hyperaldosteronism. Endocrine-Related Cancer 23: 437–454.

Einholm, A.P., Andersen, J.P. & Vilsen, B. 2007. Importance of Leu (99) in transmembrane segment M1 of the Na+, K+-ATPase in the binding and occlusion of K+. Journal of BiologicalChemistry 282: 23854–23866.

Fernandes-Rosa, F.L., Williams, T.A., Riester, A., Steichen, O., Beuschlein, F., Boulkroun, S., Strom, T.M., Monticone, S., Amar, L., Meatchi, T., Mantero, F., Cicala, M.V., Quinkler, M., Fallo, F., Allolio, B., Bernini, G., Maccario, M., Giacchetti, G., Jeunemaitre, X., Mulatero, P., Reincke, M. & Zennaro, M.C. 2014. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension 64:354–361.

Funder, J.W., Carey, R.M., Fardella, C., Gomez-Sanchez, C.E., Mantero, F., Stowasser, M., Young, W.F. & Montori, V.M. 2008. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism 93:3266–3281.

Funder, J.W. 2012. The genetic basis of primary aldosteronism. Current Hypertension Reports 14: 120–124.

Funder, J.W., Carey, R.M., Mantero, F., Murad, M.H., Reincke, M., Shibata, H., Stowasser, M. & Young, W. F. 2016. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101(5):1889–1916.

Garty, H. & Palmer, L.G. 1997. Epithelial sodium channels: function, structure, and regulation. Physiological Reviews 77:359–396.

Kuppusamy, M., Caroccia, B., Stand, J., Bandulik, S., Lenzini, L., Gioco, F., Fishman, V., Zanotti, G., Gomez-Sanchez, C., Bader, M., Warth, R. & Rossi, G.P. 2014. A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium. J Clin Endocrinol Metab 99: E1765–E1773.

Monticone, S., Hattangady, N.G., Nishimoto, K., Mantero, F., Rubin, B., Cicala, M.V., Pezzani, R., Auchus, R.J., Ghayee, H.K., Shibata, H., Kurihara, I., Williams, T.A., Giri, J.G., Bollag, R.J., Edwards, M.A., Isales, C.M. & Rainey, W.E. 2012. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab 97(8): E1567–E1572.

Morgan, L., Pipkin, F.B. & Kalsheker, N. 1996. Angiotensinogen: molecular biology, biochemistry and physiology. International Journal of Biochemistry & Cell Biology 28: 1211–1222.

Mulatero, P., Tauber, P., Zennaro, M. C., Monticone, S., Lang, K., Beuschlein, F., Fischer, E., Tizzani, D., Pallauf, A., Viola, A., Amar, L., Williams, T. A., Strom, T. M., Graf, E., Bandulik, S., Penton, D., Plouin, P-F., Warth, R., Allolio, B., Jeunemaitre, X.,Veglio, F. & Reincke, M. 2012. KCNJ5 mutations in European families with non-glucocorticoid remediable familial hyperaldosteronism. Hypertension 59(2):235–240.

Nishikawa, T., Omura, M., Satoh, F., Shibata, H., Takahashi, K., Tamura, N., Tanabe, A. & Soc, J. E. 2011. Guidelines for the diagnosis and treatment of primary aldosteronism – The Japan Endocrine Society 2009. Endocrine Journal 58:711–721.

Nishimoto, K., Tomlins, S.A., Kuick, R., Cani, A.K., Giordano, T.J., Hovelson, D. H., Liu, C.J., Sanjanwala, A.R., Edwards, M.A., Gomez-Sanchez, C.E., Nanba, K., Rainey, W.E. 2015. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proceedings of the National Academy of Sciences of the United States of America 112(33): E4591–E4599.

Omata, K., Anand, S.K., Hovelson, D.H., Liu, C.-J., Yamazaki, Y., Nakamura, Y., Ito, S., Satoh, F., Sasano, H., Rainey, W.E. & Tomlins, S. A. 2017. Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate with Age in Normal Adrenals. Journal of the Endocrine Society 1(7): 787–799.

Omata, K., Satoh, F., Morimoto, R., Ito, S., Yamazaki, Y., Nakamura, Y., Anand, S.K., Guo, Z., Stowasser, M., Sasano, H., Tomlins, S. A. & Rainey, W. E. 2018. Cellular and genetic causes of idiopathic hyperaldosteronism. Hypertension 72(4): 874–880.

Pinggera, A., Lieb, A., Benedetti, B., Lampert, M., Monteleone, S., Liedl, K.R., Tuluc, P. & Striessnig, J. 2015. CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biological Psychiatry 77: 816–822.

Rossier, B.C., Staub, O. & Hummler, E. 2013. Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: importance in the control of blood pressure and hypertension. FEBS Letters 587:1929–1941.

Scholl, U.I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R. J., Dillon, M.J., Couch, R., Hammer, L.K., Harley, F.L., Farhi, A.,Wang,W-H. & Lifton, R. P. 2012. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. PNAS 109:2533–2538.

Scholl, U.I., Goh, G., Stolting, G., de Oliveira, R.C., Choi, M., Overton, J.D., Fonseca, A.L., Korah, R., Starker, L.F., Kunstman, J.W., Prasad, M. L., Hartung, E. A., Mauras, N., Benson, M. R., Brady, T., Shapiro, J. R., Loring, E., Nelson-Williams, C., Libutti, S. K., Mane, S., Hellman, P., Westin, G., Åkerström, G., Björklund, P., Carling, T., Fahlke, C., Hidalgo, P. & Lifton, R. P. 2013. Somatic and germline CACNA1D calcium channel mutations in aldosterone producing adenomas and primary aldosteronism. Nature Genetics 451050–1054.

Scholl, U.I., Healy, J. M., Thiel, A., Fonseca, A. L., Brown, T. C., Kunstman, J.W., Horne, M.J., Dietrich, D., Riemer, J., K€uc€ukk€oyl€u, S., Reimer, E. N., Reis, A-C., Goh, G., Kristiansen, G., Mahajan, A., Korah, R., Lifton, R.P., Prasads, M. L. & Carling, T. 2015. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological, and pathological phenotype. Clinical Endocrinology 83:779–789.

Spat, A. 2004. Glomerulosa cell – a unique sensor of extracellular K+ concentration. Molecular and Cellular Endocrinology 217:23–26.

Stindl, J., Tauber, P., Sterner, C., Tegtmeier, I., Warth, R. & Bandulik, S. 2015. Pathogenesis of adrenal aldosterone-producing adenomas carrying mutations of the Na+/K+-ATPase. Endocrinology 156: 4582–4591.

Tanabe, A., Naruse, M., Arai, K., Naruse, K., Yoshimoto, T., Seki, T., Imaki, T., Kobayashi, M., Miyazaki, H. & Demura, H. 1998. Angiotensin II stimulates both aldosterone secretion and DNA synthesis via type 1 but not type 2 receptors in bovine adrenocortical cells. Journal of Endocrinological Investigation 21: 668–672.

Teo, A. E., Garg, S., Shaikh, L. H., Zhou, J., Karet Frankl, F.E., Gurnell, M., Happerfield, L., Marker, A., Bienz, M., Azizan, E.A. & Brown, M.J. 2015. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations. Journal the New England journal of medicine 373: 1429–1436.

Wang, B., Li, X., Zhang, X., Ma, X., Chen, L., Zhang, Y., Lyu, X., Tang, Y., Huang, Q., Gao, Y., Fan, Y. & Ouyang, J. 2015. Prevalence and characterization of somatic mutations in Chinese aldosterone-producing adenoma patients. Medicine 2015: 94:e708.

Williams, T. A., Monticone, S., Schack, V. R., Stindl, J., Burrello, J., Buffolo, F., Annaratone, L., Castellano, I., Beuschlein, F., Reincke, M., Lucatello, B., Ronconi, V., Fallo, F., Bernini, G., Maccario, M., Giacchetti, G., Veglio, F., Warth, R., Vilsen, B. & Mulatero, P. 2014. Somatic ATP1A1, ATP2B3, and KCNJ5 Mutations in Aldosterone-Producing Adenomas. Hypertension 63(1):188–195.

Wu, V. C., Wang, S. M., Chueh, S. J., Yang, S. Y., Huang, K. H., Lin, Y. H., Wang, J.J., Connolly, R., Hu, Y.H., Gomez-Sanchez, C.E., Peng, K.Y. & Wu, K.D. 2017. The prevalence of CTNNB 1 mutations in primary aldosteronism and consequences for clinical outcomes. Sci Rep 7:39121.

Zheng, F.F., Zhu, L. M., Nie, A. F., Li, X.Y., Lin, J. R., Zhang, K., Chen, J., Zhou, W. L., Shen, Z.J., Zhu, Y.C., Wang, J.G., Zhu, D.L. & Gao, P. J. 2015. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension 65:622–628.

Zhou, J., Azizan, E.A.B, Cabrera, C.P., Fernandes-Rosa, F.L, Boulkroun, S., Argentesi, G., Cottrell, E., Amar, L., Wu, X., O’Toole, S., Goodchild, E., Marker, A., Senanayake, R., Garg, S., Åkerström, T., Backman, S., Jordan, S., Polubothu, S., Berney, D.M., Gluck, A., Lines, K.E., Thakker, R.V., Tuthill, A., Joyce, C., Kaski, J.P., Frankl, F.E.K, Metherell, L.A., Teo, A.E.D., Gurnell, M., Parvanta, L., Drake, W.M., Wozniak, E., Klinzing, D., Kuan, J.L,, Tiang, Z., Gomez Sanchez, C.E., Hellman, P., Foo, R.S.Y., Mein, C.A., Kinsler, V.A., Björklund, P., Storr, H.L., Zennaro, M-C & Brown, M.J. 2021. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Nature Genetics 53:1360-1372.

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2024-02-13

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Review Article

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Somatic Mutations in Primary Aldosteronism - The Most Common Cause for Secondary Hypertension. (2024). Malaysian Journal of Human Genetics, 2(2), 13-24. https://mjhg.kk.usm.my/index.php/journal/article/view/28

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