Funktionelle Charakterisierung neu identifizierter Gene mit Einfluss auf das Renin-Angiotensin-Aldosteron System
Final Report Abstract
In summary, we have provided evidence for a functional impact of SLC26A2 on aldosterone secretion. As evident from a population based GWAS study and expression analysis it can be concluded that any impediment to the SLC26A2 function may contribute to development of secondary hypertension in the context of autonomous aldosterone production in primary aldosteronism. Whether this gene might be involved in rare familial cases of primary aldosteronism or as a modifier of sporadic forms of the disease will require further genetic and epidemiological studies. We could further show that somatic mutations in ATP1A1 and ATP2B3 are present in roughly 7% of aldosterone producing adenomas. In both cases inactivation of the pump function either indirectly - in the case of ATP1A1 - or directly - for ATP2B3 – are predicted to increase intracellular Ca2+ levels, which in turn prime Ca2+ - dependent signalling and aldosterone output. As the mutations identified in both ATPases are constrained to specific and highly conserved functional domains further gain of function mechanisms such as cation influx are likely to contribute to the molecular phenotype. Thereby, these findings expand the spectrum of somatic mutations leading to APAs to two members of the P-type ATPase pump family, extend our knowledge on the molecular mechanism leading to aldosterone producing adenomas and point towards novel potential therapeutic targets for the most frequent secondary form of arterial hypertension. Exploration of the pathophysiology and underlying genetics of arterial hypertension are of high socioeconomic importance. A number of genetic mechanisms underlying autonomous aldosterone secretion could be elucidated – mainly in the context of aldosterone producing adenomas. It will be of particular importance in the future to further gain insights in genetic contributors of the bilateral form of primary aldosteronism.
Publications
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KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012 Feb;59(2):235-40. Epub 2011 Dec 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
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Observational study mortality in treated primary aldosteronism: the German Conn's registry. Hypertension. 2012 Sep;60(3):618-24. Epub 2012 Jul 23
Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, Quinkler M, Hanslik G, Lang K, Hahner S, Allolio B, Meisinger C, Holle R, Beuschlein F, Bidlingmaier M, Endres S; German Conn's Registry-Else Kröner-Fresenius-Hyperaldosteronism Registry
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Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension. 2012 Mar;59(3):592-8. Epub 2012 Jan 23
Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, Mulatero P, Samson-Couterie B, Hahner S, Quinkler M, Fallo F, Letizia C, Allolio B, Ceolotto G, Cicala MV, Lang K, Lefebvre H, Lenzini L, Maniero C, Monticone S, Perrocheau M, Pilon C, Plouin PF, Rayes N, Seccia TM, Veglio F, Williams TA, Zinnamosca L, Mantero F, Benecke A, Jeunemaitre X, Reincke M, Zennaro MC
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Lack of influence of somatic mutations on steroid gradients during adrenal vein sampling in aldosterone-producing adenoma patients. Eur J Endocrinol. 2013 Oct 1;169(5):657-63. Print 2013 Nov.
Oßwald A, Fischer E, Degenhart C, Quinkler M, Bidlingmaier M, Pallauf A, Lang K, Mussack T, Hallfeldt K, Beuschlein F, Reincke M
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Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013 Apr;45(4):440-4. Epub 2013 Feb 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
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Diastrophic Dysplasia Sulfate Transporter (SLC26A2) Is Expressed in the Adrenal Cortex and Regulates Aldosterone Secretion. Hypertension. 2014 Mar 3 [Epub ahead of print]
Spyroglou A, Bozoglu T, Rawal R, De Leonardis F, Sterner C, Boulkroun S, Benecke AG, Monti L, Zennaro MC, Petersen AK, Döring A, Rossi A, Bidlingmaier M, Warth R, Gieger C, Reincke M, Beuschlein F
