LINKAGE DISEQUILIBRIUM BETWEEN THE M470V VARIANT AND THE IVS8 POLYT ALLELES OF THE CFTR GENE IN CBAVD

Congenital bilateral absence of the vas deferens (CBAVD) is a cause of male sterility mostly resulting from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The most common defect is the 5T variant at the branch/acceptor site of intron 8, which induces high l evels of exon 9 skipping leading to non-functional protein. However, t his 5T variant has incomplete penetrance and variable expressivity, su ggesting that some other regulatory factors may modulate the splicing of exon 9. To identify such factors, we report here the genetic analys is of a polymorphic locus, M470V, located in exon 10 of the CFTR gene in 60 patients with CBAVD, compared to a normal control population. Th e statistical analysis showed strong linkage disequilibrium between th e 5T allele and the V allele of the M470V polymorphism in the CBAVD po pulation, but not in the normal population. The V allele in a gene car rying 5T could, however, contribute to lowering the level of normal tr anscripts, as already suggested by in vitro transcriptional studies. T hese genetic findings, together with previous studies, suggest involve ment of the M470V variant in the modulation of the splicing of exon 9 of the CFTR gene.