MUTATIONS IN THE CYSTIC-FIBROSIS GENE IN PATIENTS WITH CONGENITAL ABSENCE OF THE VAS-DEFERENS

Background. Congenital bilateral absence of the vas deferens (CBAVD) i s a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. The molecular basis of CBAVD is not completely understood. Although p atients with cystic fibrosis have mutations in both copies of the CFTR gene, most patients with CBAVD have mutations in only one copy of the gene. Methods. To investigate CBAVD at the molecular level, we have c haracterized the mutations in the CFTR gene in 102 patients with this condition. None had clinical manifestations of cystic fibrosis. We als o analyzed a DNA variant (the 5T allele) in a noncoding region of CFTR that causes reduced levels of the normal CFTR protein. Parents of pat ients with cystic fibrosis, patients with types of infertility other t han CBAVD, and normal subjects were studied as controls. Results. Nine teen of the 102 patients with CBAVD had mutations in both copies of th e CFTR gene, and none of them had the 5T allele. Fifty-four patients h ad a mutation in one copy of CFTR, and 34 of them (63 percent) had the 5T allele in the other CFTR gene. In 29 patients no CFTR mutations we re found, but 7 of them (24 percent) had the 5T allele. In contrast, t he frequency of this allele in the general population was about 5 perc ent. Conclusions. Most patients with CBAVD have mutations in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene wi th a cystic fibrosis mutation in the other copy is the most common cau se of CBAVD. The 5T allele mutation has a wide range of clinical prese ntations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and in fertile men.