title: A naturally occurring sequence variation that creates a YY1 element is associated with increased cystic fibrosis transmembrane conductance regulator gene expression.
abstract: We have identified previously a novel complex mutant allele in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a patient affected with cystic fibrosis (CF). This allele contained a mutation in CFTR exon 11 known to cause CF (S549R(T>G)), associated with the first alteration described so far in the minimal CFTR promoter region (-102T>A). Studies on genotype-phenotype correlations revealed striking differences between patients carrying mutation (S549R(T>G)) alone, who had a severe disease, and patients carrying the complex allele (-102(T>A)+S549R(T>G)), who exhibited milder forms of CF. We thus postulated that the sequence change (-102T>A) may attenuate the effects of the severe (S549R(T>G)) mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wild-type and -102A variant human CFTR-directed luciferase reporter genes demonstrates that constructs containing the -102A variant (which creates a Yin Yang 1 (YY1) core element) increases CFTR expression significantly. Electrophoretic mobility shift assays indicate that the -102 site is located in a region of multiple DNA-protein interactions and that the -102A allele recruits specifically an additional nuclear protein related to YY1. The finding that the YY1-binding allele causes a significant increase in CFTR expression in vitro may allow a better understanding of the milder phenotype observed in patients who carry a severe CF mutation within the same gene.
authors.affiliation: Laboratoire de Génétique Moléculaire, Centre Spitalier Universitaire, 34060 Montpellier.
authors.forename: M C
authors.initials: MC
authors.lastname: Romey
authors.forename: N
authors.initials: N
authors.lastname: Pallares-Ruiz
authors.forename: A
authors.initials: A
authors.lastname: Mange
authors.forename: C
authors.initials: C
authors.lastname: Mettling
authors.forename: R
authors.initials: R
authors.lastname: Peytavi
authors.forename: J
authors.initials: J
authors.lastname: Demaille
authors.forename: M
authors.initials: M
authors.lastname: Claustres
mesh_terms: D000483:Alleles; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D050986:YY1 Transcription Factor
chemical_list: C505032:CFTR protein, human; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator