Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension
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DOI：
10.1038/ng.2550
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发表时间：
2013-04-01
期刊：
影响因子：
30.8
通讯作者：
Reincke, Martin
中科院分区：
文献类型：
--
作者：
Beuschlein, Felix;Boulkroun, Sheerazed;Reincke, Martin
原发性醛固酮增多症是继发性高血压最常见的形式。为了探索醛固酮自主分泌的分子机制，我们对产生醛固酮的腺瘤（APA）进行了外显子组测序。我们分别在 9 个 APA 中的 3 个和 2 个中鉴定出 ATP1A1（编码 Na+/K+ ATPase（1 个亚基）和 ATP2B3（编码 Ca2+ ATPase）基因的体细胞热点突变。这些 ATPase 在肾上腺细胞中表达，控制钠、钾和钙离子稳态。ATP1A1 突变体的功能性体外研究显示泵活性丧失，对钾的亲和力大大降低。对原发性肾上腺腺瘤细胞的研究为 ATP 酶改变的细胞的不适当去极化提供了进一步的证据，在 308 个 APA 中，我们发现 ATP1A1 中有 16 个（5.2％）体细胞突变，ATP2B3 中有 5 个（1.6％）突变阳性病例显示出男性优势，血浆醛固酮浓度升高，钾浓度低于突变阴性病例。 ATP酶基因家族导致醛固酮自主分泌。
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.