Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens

Abstract

Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%-2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the "5T" allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for delta F508 and none was compound heterozygous for delta F508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for delta F508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the "5T allele" was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G-->A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

Assessing the Disease-Liability of Mutations in CFTR

“…Other groups confirmed the presence of two CFTR mutations in a subset of males with CBAVD (De Braekeleer and Ferec 1996;Wilschanski et al 1996). However, the distribution of CFTR mutations differed between those with CF and those with CBAVD (Dörk et al 1997;Claustres et al 2000). The most frequent is a poly T tract polymorphism located in intron 8 (namely, the IVS8-5T) in the noncoding sequence of the gene, which is an exon 9 splice variant (Chilló n et al 1995).…”

Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs

“…Homozygous CBAVD individuals show one severe and one mild pathogenic mutation or two mild mutations, but never two severe mutations. 6 -10 In addition to classic CFTR mutations, up to 40% of CBAVD patients show the 5T allele, that is, five thymidines within intron 8, 7,8,11,12 which results in a reduction of the splicing efficiency of the CFTR gene. 13 This polymorphism is usually found with a 5 -10% prevalence in the general population.…”

CFTR gene mutations in sarcoidosis

“…The frequency of R75Q heterozygosity in the group of unrelated founders (parents) was 0.057 (three in 53), which was slightly higher but statistically not significantly different (P=0.5; Fisher's exact test) from the frequency of 0.011 (four in 94) among healthy German controls. 10 The frequency for R75Q among patients was 0.05 (eight in 138), which was statistically neither different compared to the group of healthy controls (P=0.43) nor to the parents (P=0.64) nor to the healthy siblings (P=0.35). To stratify for non-related patients, we randomly selected one patient from each family.…”

“…Instead, R75Q segregated independently from the sarcoidosis phenotype in these families. Previously, we and others reported a relatively high frequency of R75Q among patients with congenital absence of the vas deferens (CAVD), 10,17,18 bronchiectasis, 7,19 atypical mild cystic fibrosis, 20 chronic idiopathic pancreatitis, 21 allergic bronchopulmonary aspergillosis, 22 and sarcoidosis. 7,8 Bombieri et al concluded from their study that R75Q may be a CFTR gene mutation characteristic of sarcoidosis.…”

“…R75Q (G?A at nucleotide position 356) creates a new Bsr DI cleavage site in the mutated gene sequence. DNA from a R75Q heterozygous subject from a previous study 10 was used as control DNA. The subset of 54 patients was analysed for 34 mutations of the CFTR gene that are known to affect the function of the gene.…”