A Novel Point Mutation in the KCNJ5 Gene Causing Primary Hyperaldosteronism and Early-Onset Autosomal Dominant Hypertension
A Novel Point Mutation in the KCNJ5 Gene Causing Primary Hyperaldosteronism and Early-Onset Autosomal Dominant Hypertension
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DOI：
10.1210/jc.2012-1334
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发表时间：
2012-08-01
影响因子：
5.8
通讯作者：
Chrousos, George P.
中科院分区：
文献类型：
--
作者：
Charmandari, Evangelia;Sertedaki, Amalia;Chrousos, George P.
背景：肾小球肾上腺带醛固酮的产生主要受血管紧张素II、[K+]和ACTH的调节。小鼠中K+选择性泄漏（KCNK）通道与twik相关的酸敏感K+-1和/或twik相关的酸敏感K+-3亚基的遗传缺失导致原发性高醛固酮增多症，而KCNJ5（钾内校正通道，亚家族J，成员5）基因的突变与原发性高醛固酮增多症有关，在某些情况下，与人类自主肾小球细胞增殖有关。目的：本研究旨在探讨KCNK3、KCNK5、KCNK9和KCNJ5基因在原发性高醛固酮增多症和早发性高血压家族中的作用。患者和方法：2例患者，母亲和女儿，表现为严重的原发性高醛固酮增多症，双侧大量肾上腺增生，早发性高血压难治性药物治疗。分离基因组DNA，对上述基因的整个编码区外显子进行扩增和测序。进行电生理研究以确定已识别的突变对膜反转电位的影响。结果：KCNJ5基因测序显示，在核苷酸位置470 （n.G470T）出现单一杂合的鸟嘌呤取代胸腺嘧啶（G - b> T），导致异亮氨酸(I)取代丝氨酸(S)在氨基酸157 （p.I157S）。这种突变导致离子选择性丧失，细胞膜去极化，肾上腺肾小球细胞Ca2+进入增加，醛固酮合成增加。KCNK3、KCNK5和KCNK9基因的测序显示，在我们的患者中没有突变。结论：这些发现解释了一部分严重高血压患者的发病机制，并暗示了K+通道选择性在构成性醛固酮产生中的丧失。[J] .中华内分泌杂志，2012,31(5):532- 539。
Context: Aldosterone production in the adrenal zona glomerulosa is mainly regulated by angiotensin II, [K+], and ACTH. Genetic deletion of subunits of K+-selective leak (KCNK) channels TWIK-related acid sensitive K+-1 and/or TWIK-related acid sensitive K+-3 in mice results in primary hyperaldosteronism, whereas mutations in the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene are implicated in primary hyperaldosteronism and, in certain cases, in autonomous glomerulosa cell proliferation in humans.Objective: The objective of the study was to investigate the role of KCNK3, KCNK5, KCNK9, and KCNJ5 genes in a family with primary hyperaldosteronism and early-onset hypertension.Patients and Methods: Two patients, a mother and a daughter, presented with severe primary hyperaldosteronism, bilateral massive adrenal hyperplasia, and early-onset hypertension refractory to medical treatment. Genomic DNA was isolated and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials.Results: Sequencing of the KCNJ5 gene revealed a single, heterozygous guanine to thymine (G -> T) substitution at nucleotide position 470 (n.G470T), resulting in isoleucine (I) to serine (S) substitution at amino acid 157 (p.I157S). This mutation results in loss of ion selectivity, cell membrane depolarization, increased Ca2+ entry in adrenal glomerulosa cells, and increased aldosterone synthesis. Sequencing of the KCNK3, KCNK5, and KCNK9 genes revealed no mutations in our patients.Conclusions: These findings explain the pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive aldosterone production. (J Clin Endocrinol Metab 97: E1532-E1539, 2012)