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

Felice Amato, Manuela Seia, Sonia Giordano, Ausilia Elce, Federica Zarrilli, Giuseppe Castaldo, Rossella Tomaiuolo

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere60448
JournalPLoS One
Volume8
Issue number3
DOIs
Publication statusPublished - Mar 26 2013

Fingerprint

cystic fibrosis
MicroRNAs
microRNA
Cystic Fibrosis
Genes
mutation
Mutation
Scanning
Cystic Fibrosis Transmembrane Conductance Regulator
Chloride Channels
genes
3' Untranslated Regions
Gene expression
Chlorides
Alleles
alleles
chloride channels
sweat
Inborn Genetic Diseases
Bronchiectasis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gene Mutation in MicroRNA Target Sites of CFTR Gene : A Novel Pathogenetic Mechanism in Cystic Fibrosis? / Amato, Felice; Seia, Manuela; Giordano, Sonia; Elce, Ausilia; Zarrilli, Federica; Castaldo, Giuseppe; Tomaiuolo, Rossella.

In: PLoS One, Vol. 8, No. 3, e60448, 26.03.2013.

Research output: Contribution to journalArticle

Amato, Felice ; Seia, Manuela ; Giordano, Sonia ; Elce, Ausilia ; Zarrilli, Federica ; Castaldo, Giuseppe ; Tomaiuolo, Rossella. / Gene Mutation in MicroRNA Target Sites of CFTR Gene : A Novel Pathogenetic Mechanism in Cystic Fibrosis?. In: PLoS One. 2013 ; Vol. 8, No. 3.
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