title: Functional analysis of a promoter variant identified in the CFTR gene in cis of a frameshift mutation.
abstract: In monogenic diseases, the presence of several sequence variations in the same allele may complicate our understanding of genotype-phenotype relationships. We described new alterations identified in a cystic fibrosis (CF) patient harboring a 48C>G promoter sequence variation associated in cis of a 3532AC>GTA mutation and in trans with the F508del mutation. Functional analyses including in vitro experiments confirmed the deleterious effect of the 3532GTA frameshift mutation through the creation of a premature termination codon. The analyses also revealed that the 48G promoter variant has a negative effect on both transcription and mRNA level, thus demonstrating the importance of analyzing all mutations or sequence variations with potential impact on CF transmembrane conductance regulator processing, even when the two known disease-causing mutations have already been detected. Our results emphasize the need to perform, wherever possible, functional studies that may greatly assist the interpretation of the disease-causing potential of rare mutation-associated sequence variations.
authors.affiliation: INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France.
authors.forename: Victoria
authors.initials: V
authors.lastname: Viart
authors.forename: Marie
authors.initials: M
authors.lastname: Des Georges
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Magali
authors.initials: M
authors.lastname: Taulan
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D006801:Humans; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator