KCNJ5 Mutations in European Families With Nonglucocorticoid Remediable Familial Hyperaldosteronism
KCNJ5 Mutations in European Families With Nonglucocorticoid Remediable Familial Hyperaldosteronism
复制标题
DOI：
10.1161/hypertensionaha.111.183996
复制
发表时间：
2012-02-01
期刊：
影响因子：
8.3
通讯作者：
Reincke, Martin
中科院分区：
文献类型：
--
作者：
Mulatero, Paolo;Tauber, Philipp;Reincke, Martin
原发性醛固酮增多症是内分泌性高血压最常见的病因。三种形式的家族性高醛固酮增多症（FH）已被描述，命名为FH- i至-III。最近，KCNJ5的突变已被证明与FH-III相关，而FH-II的病因尚不清楚。在这项研究中，我们在21个FH家族的46例患者中寻找KCNJ5突变，其中FH- i被排除在外。我们在来自意大利一个家庭的2名原发性醛固酮增多症患者中发现了一个新的种系G151E突变，在醛固酮产生腺瘤中发现了3个体细胞突变，T158A先前被描述为与FH-III相关的种系突变，G151R和L168R都被描述为醛固酮产生腺瘤的体细胞突变。G151E突变家族的表型与先前描述的美国家族相比，在临床和生化参数方面都要温和得多。此外，体细胞KCNJ5突变的患者表现出与散发性原发性醛固酮增多症难以区分的表型。体外对G151E突变影响的功能表征显示，通道功能发生了深刻的改变，丧失了K+选择性、Na+内流和膜去极化。这些改变被认为是电压门Ca2（+）通道激活、胞质钙增加、醛固酮产生和肾上腺细胞增殖的刺激的原因。总之，我们在此描述了与FH-III相关的KCNJ5钾通道的一个新突变，该突变负责通道功能的显着改变，但与轻微的临床和激素表型相关。[j] .高血压杂志，2012;59:235-240。在线数据补充
Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism-affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K+ selectivity, Na+ influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca2(+) channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype. (Hypertension. 2012; 59: 235-240.). Online Data Supplement