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.

TLDR

The T5 allele at the polymorphic Tn locus in CFTR is a frequent disease mutation with incomplete penetrance in congenital bilateral absence of the vas deferens, and over 120 other CFTR polymorphisms have been identified. The study aimed to test whether combinations of specific polymorphic alleles could produce insufficient CFTR function. The T5 allele generates a high proportion of CFTR transcripts lacking exon 9, producing proteins that fail to contribute to apical chloride channel activity. Analysis of Tn, TG, and M470V loci revealed that TG repeats and the M470V variant modulate transcript skipping and protein activity, with TG11/12 increasing exon‑9‑skipped transcripts, high TG repeats in T5 patients, and M470 proteins showing slower maturation but 1.7‑fold higher chloride activity, thereby explaining partial penetrance and phenotypic variability.

Abstract

In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.