EXTENSIVE ANALYSIS OF 40 INFERTILE PATIENTS WITH CONGENITAL ABSENCE OF THE VAS-DEFERENS - IN 50-PERCENT OF CASES ONLY ONE CFTR ALLELE COULDBE DETECTED

Mutations in the cystic fibrosis (CF) conductance transmembrane regula tor (CFTR) gene have been detected in patients with CF and in males wi th infertility attributable to congenital bilateral absence of the vas deferens (CBAVD). Thirty individuals with CBAVD and 10 with congenita l unilateral absence of the vas deferens (CUAVD) were analyzed by sing le-strand conformation analysis and denaturing gradient gel electropho resis for mutations in most of the CFTR gene. All 40 individuals were pancreatic sufficient, but twenty patients had recurrent or sporadic r espiratory infections, asthma/asthmatic bronchitis, and/or rhino-sinus itis. Agenesia or displasia of one or both seminal vesicles was detect ed in 30 men and other urogenital malformations were present in six su bjects. Among the 40 samples, we identified 13 different CFTR mutation s, two of which were previously unknown. One new mutation in exon 4 wa s the deletion of glutamic acid at codon 115 (Delta E115). A second ne w mutation was found in exon 17b, viz., an A-->C substitution at posit ion 3311, changing lysine to threonine at codon 1060 (K1060T). CFTR mu tations were detected in 22 out of 30 (73.3%) CBAVD patients and in on e out of 10 (10%) CUAVD individuals, showing a significantly lower inc idence of CFTR mutations in CBAVD/CUAVD patients (P much less than 0.0 001), compared with that found in the CF patient population. Only thre e CBAVD patients were found with more than one CFTR mutation (Delta F5 08/L206W, Delta F508/R74W + D1270N, R117H/712-1G-->T), highlighting L2 06W, R74W/D1270N, and R117H as benign CF mutations. Sweat electrolyte values were increased in 76.6% of CBAVD patients, but three individual s without CFTR mutations had normal sweat electrolyte levels (10% of t he total CBAVD patients), suggesting that factors other than CFTR muta tions are involved in CBAVD. The failure to identify a second mutation in exons and their flanking regions of the CFTR gene suggests that th ese mutations could be located in introns or in the promoter region of CFTR. Such mutations could result in CFTR levels below the minimum 6% -10% necessary for normal protein function.