Premium
Disrupted posttranscriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5′UTR mutation is associated with a cftr‐related disease
Author(s) -
Lukowski Samuel W.,
Bombieri Cristina,
Trezise Ann E. O.
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21545
Subject(s) - cystic fibrosis transmembrane conductance regulator , biology , genetics , mutation , cystic fibrosis , untranslated region , gene , coding region , phenotype , open reading frame , five prime untranslated region , microbiology and biotechnology , messenger rna , peptide sequence
Cystic fibrosis (CF) is characterized as a single‐gene disorder with a simple, autosomal recessive mode of inheritance. However, translation of cystic fibrosis transmembrane conductance regulator ( CFTR ) genotype into CF phenotype is influenced by nucleotide sequence variations at multiple genetic loci, and individuals heterozygous for CFTR mutations are predisposed to a range of CFTR ‐related conditions, such as disseminated bronchiectasis. CF disease severity and CFTR ‐related conditions are more akin to complex, multifactorial traits, which are increasingly being associated with mutations that perturb gene expression. We have identified a patient with disseminated bronchiectasis, who is heterozygous for a single‐nucleotide substitution in the CFTR 5′ untranslated region (UTR) (c.‐34C>T). The c.‐34C>T mutation creates an upstream AUG codon and upstream open reading frame that overlaps, and is out of frame with, the CFTR protein coding sequence. Using luciferase reporter constructs, we have shown that the c.‐34C>T mutation decreases gene expression by 85–99%, by reducing translation efficiency and mRNA stability. This is the first CFTR regulatory mutation shown to act at a posttranscriptional level that reduces the synthesis of normal CFTR (Class V), and reaffirms the importance of regulatory mutations as a genetic basis of multifactorial phenotypes. ©2011 Wiley‐Liss, Inc.