title: Disrupted post-transcriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5'UTR mutation is associated with a CFTR-related disease.
abstract: 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.
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Australia.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Lukowski
authors.forename: Cristina
authors.initials: C
authors.lastname: Bombieri
authors.forename: Ann E O
authors.initials: AE
authors.lastname: Trezise
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D001483:Base Sequence; D001987:Bronchiectasis / Q000235:genetics; D002460:Cell Line; D018387:Codon, Initiator; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D023061:Gene Order; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010442:Peptide Chain Initiation, Translational; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D016415:Sequence Alignment
chemical_list: D020121:5' Untranslated Regions; D018387:Codon, Initiator; D019005:Cystic Fibrosis Transmembrane Conductance Regulator