Mol. Hum. Reprod. Advance Access originally published online on September 14, 2006
Molecular Human Reproduction 2006 12(11):717-721; doi:10.1093/molehr/gal077
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Two novel missense and one novel nonsense CFTR mutations in Iranian males with congenital bilateral absence of the vas deferens
1Department of Reproductive Genetics, 2Department of Male Infertility, Reproductive Biomedicine Research Center of Royan Institute, 3Genetic Research Center of Social Welfare and Rehabilitation Sciences University and 4Department of Stem Cell, Reproductive Biomedicine Research Center of Royan Institute, Tehran, Iran
5 To whom correspondence should be addressed at: Department of Reproductive Genetics, Reproductive Biomedicine Research Center of Royan Institute, PO Box 19395-4644, Tehran, Iran. E-mail: rradpour{at}royaninstitute.org
Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia. Nearly 75% of men with CBAVD have at least one detectable common cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutation. To study the involvement of CFTR mutations in the Iranian population with presumed low CF frequency, we analysed 112 Iranian CBAVD males. Three Iranian CBAVD males with no clinical CF phenotype indicated by a normal karyotype, normal pancreatic function and sweat chloride concentration and no Y chromosome microdeletions were studied for CFTR mutations, IVS8-5T mutations and M470V exon 10 missense polymorphism. The entire coding sequence of each gene was analysed using a combination of the denaturing gradient-gel electrophoresis or by single-strand conformation analysis and direct DNA sequencing. Also, 52 fertile males were tested as controls to rule out polymorphism. This approach allowed us to detect one novel nonsense mutation (K536X) in the nucleotide-binding domain 1 (NBD1) region and two novel missense mutations (Y122H and T338A) in the M2 and M6 regions of CFTR gene in our studied population, which were not reported previously. Also, the conservation of changed nucleotide and amino acid in mutated regions was analysed by aligning with nine different species. K536X nonsense mutation (transversion) was found in the first NBD (NBF1), which plays an important regulatory role in CFTR function. It was, therefore, considered as a severe allele responsible for elevated sweat chloride levels and obstructive azoospermia. Because Y122H and T338A mutations were compound heterozygote with the IVS8-5T, it is difficult to judge the severity of these mutations and their role in the CBAVD phenotype.
Key words: CBAVD/CFTR/male infertility/new mutation
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