Gene Mutation in MicroRNA Target Sites of CFTR Gene: A Novel Pathogenetic Mechanism in Cystic Fibrosis?

<div><p>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 <i>CFTR</i> gene. Also using scanning techniques to analyze the whole coding regions of <i>CFTR</i> gene, mutations are not identified in up to 10% of CF alleles, and such figure increases in <i>CFTR</i>-related disorders (<i>CFTR</i>-RD). Other gene regions may be the site of causing-disease mutations. We searched for genetic variants in the 1500 bp of <i>CFTR</i> 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 <i>CFTR</i>-RD (n = 43) patients with one or none mutation after <i>CFTR</i> 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 <i>CFTR</i>-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 <i>in vitro</i> a reduced expression of CFTR protein. Thus, the c.*1043A>C may act as a mild <i>CFTR</i> mutation enhancing the affinity for inhibitory miRNAs as a novel pathogenetic mechanism in CF.</p>