Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

被引：423

作者：

Beuschlein, Felix ^{[1
]}

Boulkroun, Sheerazed ^{[2
,3
]}

Osswald, Andrea ^{[1
]}

Wieland, Thomas ^{[4
]}

Nielsen, Hang N. ^{[5
]}

Lichtenauer, Urs D. ^{[1
]}

Penton, David ^{[6
]}

Schack, Vivien R. ^{[5
]}

Amar, Laurence ^{[2
,3
,7
]}

Fischer, Evelyn ^{[1
]}

Walther, Anett ^{[4
]}

Tauber, Philipp ^{[6
]}

Schwarzmayr, Thomas ^{[4
]}

Diener, Susanne ^{[4
]}

Graf, Elisabeth ^{[4
]}

Allolio, Bruno ^{[8
]}

Samson-Couterie, Benoit ^{[2
,3
]}

Benecke, Arndt ^{[9
]}

Quinkler, Marcus ^{[10
]}

Fallo, Francesco ^{[11
]}

Plouin, Pierre-Francois ^{[2
,3
,7
]}

Mantero, Franco ^{[12
]}

Meitinger, Thomas ^{[4
,13
,14
]}

Mulatero, Paolo ^{[15
]}

Jeunemaitre, Xavier ^{[2
,3
,7
]}

Warth, Richard ^{[6
]}

Vilsen, Bente ^{[5
]}

Zennaro, Maria-Christina ^{[2
,3
,7
]}

Strom, Tim M. ^{[4
,13
]}

Reincke, Martin ^{[1
]}

机构：

[1] Univ Munich, Med Klin & Poliklin 4, Munich, Germany

[2] Paris Cardiovasc Res Ctr, INSERM, UMRS 970, Paris, France

[3] Univ Paris 05, Sorbonne Paris Cite, Paris, France

[4] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[5] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[6] Univ Regensburg, D-93053 Regensburg, Germany

[7] Hop Europeen Georges Pompidou, AP HP, Paris, France

[8] Univ Hosp Wurzburg, Dept Med 1, Endocrine & Diabet Unit, Wurzburg, Germany

[9] Inst Hautes Etud Sci, CNRS, F-91440 Bures Sur Yvette, France

[10] Univ Hosp Charite, Berlin, Germany

[11] Univ Padua, Dept Med, Padua, Italy

[12] Univ Padua, Dept Med, Endocrine Unit, Padua, Italy

[13] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany

[14] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany

[15] Univ Turin, Dept Med Sci, Div Internal Med & Hypertens, Turin, Italy

来源：

NATURE GENETICS | 2013年 / 45卷 / 04期

基金：

英国医学研究理事会;

关键词：

ZONA GLOMERULOSA; KCNJ5; MUTATIONS; ATPASE; PREVALENCE; PATHWAYS; CELLS; PUMP;

D O I：

10.1038/ng.2550

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase (1 subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16(5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutationnegative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

引用

页码：440 / 444

页数：5

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