A naturally occurring sequence variation that creates a YY1 element is associated with increased cystic fibrosis transmembrane conductance regulator gene expression

We have identified previously a novel complex mutant allele in the cystic f ibrosis transmembrane conductance regulator (CFTR) gene in a patient affect ed with cystic fibrosis (CF), This allele contained a mutation in CFTR exon II known to cause CF (S549R(T>G)), associated with the first alteration de scribed so far in the minimal CFTR promoter region (-102T>A), Studies on ge notype-phenotype correlations revealed striking differences between patient s carrying mutation (S549R(T>G)) alone, who had a severe disease, and patie nts carrying the complex allele (-102(T>A) + S549R(T > G)), who exhibited m ilder forms of CF. We thus postulated that the sequence change (-102T>A) ma y attenuate the effects of the severe (S549R(T>G)) mutation through regulat ion 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. Ele ctrophoretic 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 fin ding that the YY1-binding allele causes a significant increase in CFTR expr ession in vitro may allow a better understanding of the milder phenotype ob served in patients who carry a severe CF mutation within the same gene.