KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome.
KCNJ5 mutations in the National Institutes of Health cohort of patients with primary hyperaldosteronism: an infrequent genetic cause of Conn's syndrome.
复制标题
美国国立卫生研究院原发性醛固酮增多症患者队列中的 KCNJ5 突变：康恩综合征的罕见遗传原因。
DOI：
10.1530/erc-12-0022
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发表时间：
2012-06
影响因子：
3.9
通讯作者：
Stratakis CA
中科院分区：
文献类型：
--
作者：
Xekouki P;Hatch MM;Lin L;Rodrigo de A;Azevedo M;de la Luz Sierra M;Levy I;Saloustros E;Moraitis A;Horvath A;Kebebew E;Hoffman DA;Stratakis CA
KCNJ5基因突变最近被报道为原发性醛固酮增多症(PH或Conn‘s综合征)。这些突变在PH中的频率和KCNJ5缺陷导致疾病的方式仍不清楚。在过去的12年里，美国国立卫生研究院共收治了53名PH患者。对他们的外周和肿瘤DNA(后者来自16例手术患者)进行KCNJ5突变筛查；瞬时转基因后对已识别的缺陷进行功能研究。只发现了两个突变，而且都只存在于肿瘤DNA中。除了已知的KCNJ5基因同义变异外，任何患者都没有胚系测序缺陷。一个突变是先前描述的C.G451C突变，另一个是同一密码子中的一个新突变：C.G451A；两者都导致KCNJ5蛋白中相同的氨基酸替换(G151R)。功能研究证实了先前的发现，即这两个突变都会导致通道选择性的丧失和反转电位的正移。综上所述，KCNJ5蛋白在正常肾上腺的肾小球带中有较强的表达，但在有突变和无突变的醛固酮腺瘤中有不同的表达。在PH患者和/或他们的肿瘤患者中，KCNJ5突变率显著低于先前报道的。G151R氨基酸替换似乎是迄今为止在PH中检测到的最频繁的一种，尽管有额外的核苷酸变化。该突变导致该钾通道的选择性丧失，可能有助于设计治疗PH的新疗法。
KCNJ5 mutations were recently described in primary hyperaldosteronism (PH or Conn’s syndrome). The frequency of these mutations in PH and the way KCNJ5 defects cause disease remain unknown. A total of 53 patients with PH have been seen at the National Institutes of Health over the last 12 years. Their peripheral and tumor DNAs (the latter from 16 that were operated) were screened for KCNJ5 mutations; functional studies on the identified defects were performed after transient transfection. Only two mutations were identified, and both in the tumor DNA only. There were no germline sequencing defects in any of the patients except for known synonymous variants of the KCNJ5 gene. One mutation was the previously described c.G451C alteration; the other was a novel one in the same codon: c.G451A; both lead to the same amino acid substitution (G151R) in the KCNJ5 protein. Functional studies confirmed previous findings that both mutations caused loss of channel selectivity and a positive shift in the reversal potential. In conclusion, the KCNJ5 protein was strongly expressed in the zona glomerulosa of normal adrenal glands but showed variable expression in the aldosterone-producing adenomas with and without mutation. The rate of KCNJ5 mutations among patients with PH and/or their tumors is substantially lower than what was previously reported. The G151R amino acid substitution appears to be the most frequent one so far detected in PH, despite additional nucleotide changes. The mutation causes loss of this potassium channel’s selectivity and may assist in the design of new therapies for PH.