Polyvariant Mutant Genes: different haplotypes determining different alterations causing azoospermia

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Furthermore, the involvement of this gene in other pathologies „associated with CF”, like Congenital Absence of the Vas Deferens (bilateral or unilateral, CBAVD or CUAVD, resp.) is known, though the mutations causing these phenotypes within a defined population are different from those observed in CF patients. While cystic fibrosis patients have CFTR mutations in both alleles, most of the patients suffering from CF-related pathologies have mutations in only one allele. Frequently, the second CFTR allele is not mutant but polyvariant carrying a combination of alleles of polymorphic loci, called Polyvariant Mutant Genes (PMG) which, as a whole haplotype, contribute to lowering the level of CFTR transcripts. The loci involved in these PMG are Tn, TGm (both in intron 8), and M470V (exon 10) of the CFTR gene. We have carried out an exhaustive analysis of the CFTR gene in order to determine its possible role in 15 azoospermic Spanish patients. We have found that all CBAVD cases with a CF mutation carry the haplotype 5T-12(TG)-V470 on the second allele which is different from that found in other related pathologies causing azoospermia, like Congenital Bilateral Absence of Seminal Vesicles (CBASV) or CUAVD, where we have found the haplotype 5T-11(TG)-M470 which is more efficient producing CFTR protein. We believe that the latter phenotypes represent incomplete forms of CBAVD. Given the high frequency of severe CF mutations an exhaustive screening of CFTR mutations should be offered when assisted reproduction technologies are available. Moreover, when two mutations (or one mutations and a PMG) are detected, their phase should be established, since the existence of double mutants could modify the phenotype and it may suggest that the alteration in the other CFTR gene remains unidentified.