POLYVARIANT MUTANT CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENES - THE POLYMORPHIC (TG)M LOCUS EXPLAINS THE PARTIAL PENETRANCE OF THE T5 POLYMORPHISM AS A DISEASE MUTATION

In congenital bilateral absence of the vas deferens patients, the T5 a llele at the polymorphic Tn locus in the CFTR (cystic fibrosis transme mbrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportio n of CFTR transcripts that lack exon 9, whose translation products wil l not contribute to apical chloride channel activity. Besides the poly morphic Tn locus, more than 120 polymorphisms have been described in t he CFTR gene. We hypothesized that the combination of particular allel es at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with fr equent alleles in the general population showed that, in addition to t he known effect of the Tn locus, the quantity and quality of CFTR tran scripts and/or proteins was affected by two other polymorphic loci: (T G)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold i ncrease in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a six-fold increase, compared with the (TG)10 allele. T5 C FTR genes derived from patients were found to carry a high number of T G repeats, while T5 CFTR genes derived from healthy CF fathers harbore d a low number of TG repeats. Moreover, it was found that M470 CFTR pr oteins matured more slowly, and that they had a 1.7-fold increased int rinsic chloride channel activity compared with V470 CFTR proteins, sug gesting that the M470V locus might also play a role in the partial pen etrance of T5 as a disease mutation. Such polyvariant mutant genes cou ld explain why apparently normal CFTR genes cause disease. Moreover, t hey might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.