GEnetic and mechanistic studies of primary Aldosteronism

• Applicants: Professor Dr. Felix Beuschlein; Professor Dr. Martin Reincke; Privatdozent Dr. Tim-Matthias Strom
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242499380

Arterial hypertension is a major cardiovascular risk factor that affects between 10 and 40% of the population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. Among subtypes of PA, aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) together account for ~95% of cases. Somatic and inherited mutations of the potassium channel KCNJ5 have been implicated in the formation of aldosterone producing adenoma and in familial hyperaldosteronism type 3. We have shown that somatic KCNJ5 mutations are present in ~40% of APA. More recently, we have performed whole exome sequencing in a limited number of APA and identified somatic mutations in ATP1A1 and ATP2B3, which are present in ~7% of tumors. All these mutations affect the adrenal zona glomerulosa cell membrane potential, the major trigger for aldosterone production. The overall hypothesis of this proposal is that somatic or germ-line mutations are responsible for different forms of sporadic and familial PA. The aim of our program is 1) to fill the gap in our understanding of the genetic causes of PA in patients with APA not harboring mutations in the KCNJ5, ATP1A1 and ATP2B3 genes, as well as in patients with FH2 and BAH; 2) to perform mechanistic studies allowing to understand the pathogenic mechanisms of PA in relation to cell proliferation and aldosterone production; and 3) to translate these findings into clinical investigation. To achieve these objectives we will use the most recent genomic technologies available applied on unique cohorts of patients with sporadic and familial PA, with access to standardized clinical and biological information, tumor and DNA samples, integrated within the European network for the study of adrenal tumors (ENS@T), as well as original mouse models of the disease. Our strategy will integrate complementary high throughput approaches to: (1) identify further genes in APA not harboring KCNJ5 and ATPase mutations; (2) assess disease risk in PA; (3) test the hypothesis that rare exonic variants within one or few genes cause familial hyperaldosteronism type 2 (FH2) and PA in mice; (4) define the mechanisms by which candidate genes mutated in APA increase cell growth and induce tumor formation; (5) test the hypothesis that abnormal regulation of potassium channels and ATPases cause PA in patients without mutations; and (6) define the clinical impact of KCNJ5/ATP1A1/ATP2B3 and other mutations on diagnosis and outcome of patients with PA. Thereby, this project will extend our knowledge on the genetic and mechanistic determinants of PA to be translated into clinical investigation, and open new perspectives for the identification of novel potential therapeutic targets for the most frequent secondary form of arterial hypertension.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Participating Persons: Xavier Jeunemaitre, Ph.D.; Maria-Christina Zennaro