Mutations in the Amiloride-Sensitive Epithelial Sodium Channel in Patients With Cystic Fibrosis-Like Disease
Mutations in the Amiloride-Sensitive Epithelial Sodium Channel in Patients With Cystic Fibrosis-Like Disease
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DOI：
10.1002/humu.21011
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发表时间：
2009-07-01
期刊：
影响因子：
3.9
通讯作者：
Cuppens, Harry
中科院分区：
文献类型：
--
作者：
Azad, Abul Kalam;Rauh, Robert;Cuppens, Harry
我们调查了编码阿米洛利敏感上皮钠通道(ENaC)不同亚单位的基因突变是否会导致囊性纤维性变(CF)样疾病。在一小部分患者中，这种疾病可能是通过孟德尔机制的ENaC突变来解释的，例如SCNN1A中的p.V114I和p.F61L。更重要的是，在患者组中发现了几种罕见的ENaC多态的发生率(30%比对照组的9%)显著增加了三倍以上，这表明ENaC在一些患者中是通过多基因机制参与的。具体地说，处于杂合状态的SCNN1A携带c.-55+5G>；C或p.W493R的患者数量显著增加，优势比(OR)分别为13.5和2.7。W493R-SCNN1A多态甚至被发现在非洲爪哇卵母细胞中异源表达时，导致ENaC通道的活性增加四倍。在普通人群中，大约975名个体中的I将是高活性的p.W493R-SCNN1A突变和囊性纤维化跨膜传导调节(CFTR)基因的杂合子，该基因导致极低数量(0-10%)的功能性CFTR。这些ENaC/CFTR型可能在肺部疾病中发挥迄今未被认识到的作用。2009年，哼唱时间30：1093-1103。(C)2009年Wiley-Liss，Inc.
We investigated whether mutations in the genes that code for the different subunits of the amiloride-sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)-like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.F61L in SCNN1A. More importantly, a more than three-fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. Specifically, a significantly higher number of patients carried c.-55+5G > C or p.W493R in SCNN1A in the heterozygous state, with odds ratios (ORs) of 13.5 and 2.7, respectively. The p.W493R-SCNN1A polymorphism was even found to result in a four-fold more active ENaC channel when heterologously expressed in Xenopus laevis oocytes. About I in 975 individuals in the general population will be heterozygous for the hyperactive p.W493R-SCNN1A mutation and a cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in very low amounts (0-10%) functional CFTR. These ENaC/CFTR genotypes may play a hitherto unrecognized role in lung diseases. Hum Mutat 30:1093-1103, 2009. (C) 2009 Wiley-Liss, Inc.