Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected

Abstract

Mutations in the cystic fibrosis (CF) conductance transmembrane regulator (CFTR) gene have been detected in patients with CF and in males with infertility attributable to congenital bilateral absence of the vas deferens (CBAVD). Thirty individuals with CBAVD and 10 with congenital unilateral absence of the vas deferens (CUAVD) were analyzed by single-strand conformation analysis and denaturing gradient gel electrophoresis for mutations in most of the CFTR gene. All 40 individuals were pancreatic sufficient, but twenty patients had recurrent or sporadic respiratory infections, asthma/asthmatic bronchitis, and/or rhino-sinusitis. Agenesia or displasia of one or both seminal vesicles was detected in 30 men and other urogenital malformations were present in six subjects. Among the 40 samples, we identified 13 different CFTR mutations, two of which were previously unknown. One new mutation in exon 4 was the deletion of glutamic acid at codon 115 (delta E115). A second new mutation was found in exon 17b, viz., an A --> C substitution at position 3311, changing lysine to threonine at codon 1060 (K1060T). CFTR mutations were detected in 22 out of 30 (73.3%) CBAVD patients and in one out of 10 (10%) CUAVD individuals, showing a significantly lower incidence of CFTR mutations in CBAVD/CUAVD patients (P << 0.0001), compared with that found in the CF patient population. Only three CBAVD patients were found with more than one CFTR mutation (delta F508/L206W, delta F508/R74W + D1270N, R117H/712-1G --> T), highlighting L206W, R74W/D1270N, and R117H as benign CF mutations. Sweat electrolyte values were increased in 76.6% of CBAVD patients, but three individuals without CFTR mutations had normal sweat electrolyte levels (10% of the total CBAVD patients), suggesting that factors other than CFTR mutations are involved in CBAVD. The failure to identify a second mutation in exons and their flanking regions of the CFTR gene suggests that these 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.

CFTR mutation distribution among U.S. Hispanic and African American individuals: Evaluation in cystic fibrosis patient and carrier screening populations

“…29 The ⌬F508/ D1270N-R74W genotype has been reported in a girl with CF symptoms, 41 in 2 CF patients, 3 CBAVD patients, 24 and a 27-year-old man with CBAVD, elevated sweat chlorides, recurrent respiratory infection, and rhinitis. 35 Our study of 192 D1270N-positive specimens was not suggestive of a role for R74W as a modifying allele, and a definitive explanation for the variable D1270N frequencies remains unknown.…”

“…D1270N has been identified in individuals with cystic fibrosis 24,33,35,36 as well as in men with congenital absence of the vas deferens. 24,37 Similar discrepancies in mutation frequency between carrier and patient populations are now well known for the R117H 15 and I148T 38,39 sequence changes, each of which has a cis-acting modifier influencing phenotype (5T 21 and 3199del6, 40 respectively).…”

Cystic fibrosis testing 8 years on: Lessons learned from carrier screening and sequencing analysis

“…This is another variant with high prevalence in certain populations and documented atypical presentations. After sequencing 40 CBAVD patients, Bassas et al 30 concluded that L206W, R74W/D1270N, and R117H are benign CF mutations. Another report described four patients with L206W and mild CF.…”

Analysis of mutations in the cystic fibrosis transmembrane regulator (CFTR) gene in patients with obstructive azoospermia

“…Studies on CFTR protein function show that 6%-10% of the normal levels of this protein are sufficient for normal ion transport (Chu et al, 1993); therefore, carrying one mutation only would not lead to the CF phenotype. A possible explanation is that the second alter-ation could be located at non-screened intronic, promoter, or regulatory sites, resulting in a CFTR protein with normal structure but low levels of expression, thus altering the development of susceptible tissues, such as the vas deferens and epididymis (Culard et al, 1999;Casals et al, 1995;Anguiano et al, 1992). Interestingly, we recently examined a male patient presenting with alcoholic pancreatitis, who carried two CF mutations and had fathered two children (unpublished observation).…”