Gene mutation in microRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis?
Gene mutation in microRNA target sites of CFTR gene: a novel pathogenetic mechanism in cystic fibrosis?
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DOI：
10.1371/journal.pone.0060448
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tomaiuolo R
中科院分区：
文献类型：
--
作者：
Amato F;Seia M;Giordano S;Elce A;Zarrilli F;Castaldo G;Tomaiuolo R
囊性纤维化是高加索人中最常见的致死性遗传病。它依赖于大多数上皮细胞表达的、由CFTR基因编码的氯离子通道的变化。同样使用扫描技术分析CFTR基因的整个编码区，在多达10%的CF等位基因中没有发现突变，并且在CFTR相关疾病(CFTR-RD)中这样的数字增加。其他基因区域可能是导致疾病突变的部位。我们在CFTR3‘非翻译区1500bp的典型转录后基因调控靶点--CFTR3’非翻译区寻找遗传变异，包括具有F508del纯合子基因且临床表现不同的CF患者(n = 20)、CFTR3‘非翻译区(n = 32)和CFTRRD(n = 43)患者，以及对照组(n = 50)。我们确定了三个SNP，其中一个是c*1043A>；C，位于一个预测与miR-433和miR-509-3p结合的区域。这种突变是先天性双侧输精管缺如(CBAVD)、弥漫性支气管扩张、交界性汗氯化物试验和另一个等位基因F508del杂合突变的CFTRRD患者所特有的。表达分析表明，c*1043A和gt；C增加了对miR-509-3p的亲和力，而略有降低对miR-433的亲和力。这两种miRNAs在体外都导致CFTR蛋白表达减少。因此，c.*1043A>；C可能是一种轻微的CFTR突变，增强了对抑制性miRNAs的亲和力，这可能是一种新的CF发病机制。
Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians. It depends on alterations of a chloride channel expressed by most epithelial cells and encoded by CFTR gene. Also using scanning techniques to analyze the whole coding regions of CFTR gene, mutations are not identified in up to 10% of CF alleles, and such figure increases in CFTR-related disorders (CFTR-RD). Other gene regions may be the site of causing-disease mutations. We searched for genetic variants in the 1500 bp of CFTR 3′ untranslated region, typical target of microRNA (miRNA) posttranscriptional gene regulation, in either CF patients with the F508del homozygous genotype and different clinical expression (n = 20), CF (n = 32) and CFTR-RD (n = 43) patients with one or none mutation after CFTR scanning and in controls (n = 50). We identified three SNPs, one of which, the c.*1043A>C, was located in a region predicted to bind miR-433 and miR-509-3p. Such mutation was peculiar of a CFTR-RD patient that had Congenital Bilateral Absence of Vas Deferens (CBAVD), diffuse bronchiectasis, a borderline sweat chloride test and the heterozygous severe F508del mutation on the other allele. The expression analysis demonstrated that the c.*1043A>C increases the affinity for miR-509-3p and slightly decreases that for the miR-433. Both miRNAs cause in vitro a reduced expression of CFTR protein. Thus, the c.*1043A>C may act as a mild CFTR mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF.
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DOI：
10.1042/bj20110672
发表时间：
2011-08-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Gillen AE;Gosalia N;Leir SH;Harris A
通讯作者：
Harris A
DOI：
10.1002/ajmg.10461
发表时间：
2002-07-22
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Salvatore, F;Scudiero, O;Castaldo, G
通讯作者：
Castaldo, G
影响因子：
11.2
作者：
Chin LJ;Ratner E;Leng S;Zhai R;Nallur S;Babar I;Muller RU;Straka E;Su L;Burki EA;Crowell RE;Patel R;Kulkarni T;Homer R;Zelterman D;Kidd KK;Zhu Y;Christiani DC;Belinsky SA;Slack FJ;Weidhaas JB
通讯作者：
Weidhaas JB
影响因子：
30.8
作者：
Kertesz, Michael;Iovino, Nicola;Segal, Eran
通讯作者：
Segal, Eran
影响因子：
5.2
作者：
Tomaiuolo, R.;Sangiuolo, F.;Novelli, G.
通讯作者：
Novelli, G.