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.

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.

The CFTR polymorphisms poly-T, TG-repeats and M470V in Chinese males with congenital bilateral absence of the vas deferens

“…Previous studies suggested that IVS8-5T shows higher disease penetrance when it is combined with the higher number of IVS8-(TG)m. 15 It was found that 5T was in cis with three different TG repeats (TG11-5T, TG12-5T, TG13-5T). 13 In 72 cases with 97 alleles of IVS8-5T present in 109 Chinese CBAVD patients, 70 cases (97.22%) and 94 alleles (96.91%) had 12 or 13 TG repeats adjacent to 5T.…”

“…14 Another common variant in CFTR, a methionine or valine at codon 470, was suggested to influence the penetrance of 5T. 15 The quantity and quality of CFTR transcripts and/or proteins was affected by (TG)m(T)n and M470V polymorphic loci. 15 Previous studies have demonstrated that the 5T-V470 haplotype showed a higher disease association than the 5T-M470 haplotype.…”

“…15 The quantity and quality of CFTR transcripts and/or proteins was affected by (TG)m(T)n and M470V polymorphic loci. 15 Previous studies have demonstrated that the 5T-V470 haplotype showed a higher disease association than the 5T-M470 haplotype. 19,25 Cuppens et al 15 demonstrated that the V470 allele yielded a lower functional CFTR protein rate than the M470 allele, independently of the intron 8 genotypes, using in vitro studies.…”

“…19 By in vitro studies, it was shown that the CFTR gene carrying the V allele yielded a lower functional CFTR protein rate than those carrying the M allele, independently of the intron 8 Tn genotype. 15 de Meeus et al 19 reported that strong linkage disequilibrium was observed between the 5T allele and the V allele of the M470V polymorphism in the CBAVD population, but not in the normal population.…”

“…13,14 The number of TG repeats immediately adjacent to 5T is associated with a variable efficiency of exon 9 splicing. 15,16 The different alleles at (TG)m(T)n polymorphic loci at the 39 end of human CFTR intron 8 determine the exon 9 splicing efficiency. 17,18 In other respects, the M470V (1540A/G in exon 10) polymorphism is one of the most common polymorphisms in the CFTR gene.…”