title: Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.
abstract: Cystic fibrosis (CF) is usually considered a rare disease in the Indian population. Two studies have reported on the frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Indian males with congenital absence of the vas deferens (CAVD), however, data on the spectrum of CFTR gene mutations are still lacking. Therefore, the present study was designed to identify the spectrum of CFTR gene mutations as well as to investigate an association of CF genetic modifiers in the penetrance of CAVD in infertile Indian men. A total of 60 consecutive infertile males with a diagnosis of CAVD were subjected to CFTR gene analysis which revealed 13 different CFTR gene mutations and 1 intronic variant that led to aberrant splicing. p.Phe508del (n = 16) and p.Arg117His (n = 4) were among the most common severe forms of CFTR mutations identified. The IVS8-T5 allele, which is considered as a mild form of CFTR mutation, was found with an allelic frequency of 28.3%. Eight novel mutations were also identified in the CFTR gene from our patient cohort. It is noteworthy that the spectrum of CFTR gene mutation is heterogeneous, with exon 4 and exon 11 as hot spot regions. Moreover, we also found an association of the CF genetic modifiers, viz., transforming growth factor (TGF)-β1 and endothelial receptor type-A (EDNRA) genes with the CAVD phenotype. The findings are of considerable clinical significance because men suffering from infertility due to CAVD can decide to use artificial reproduction technology. The children of men with CAVD are at risk of carrying CFTR mutations; therefore, genetic counseling is a crucial step for such patients. With special reference to developing countries, such as India, where whole gene sequencing is not feasible, the outcome of our study will make the screening procedure for CFTR gene simpler and more cost-effective as we have identified hot spot regions of the CFTR gene which are more prone to mutation in Indian males with CAVD. Moreover, this is the first study from the Indian population to investigate the association of CF genetic modifiers with penetrance of the CAVD phenotype. The observed association of the genetic modifiers TGF-β1 and EDNRA in the penetrance of CAVD further supports their involvement in genesis of the vas deferens.
authors: Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors: H
authors: H
authors: Sharma
authors: Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors: R S
authors: RS
authors: Mavuduru
authors: Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors: S K
authors: SK
authors: Singh
authors: Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India fateh1977@yahoo.com.
authors: R
authors: R
authors: Prasad
mesh_terms: D000328:Adult; D000483:Alleles; D017398:Alternative Splicing; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005787:Gene Frequency; D056726:Genetic Association Studies; D005817:Genetic Counseling; D006801:Humans; D007194:India; D007248:Infertility, Male / Q000209:etiology; D007438:Introns; D008297:Male; D052801:Male Urogenital Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044022:Receptor, Endothelin A / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D014649:Vas Deferens / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C505032:CFTR protein, human; D044022:Receptor, Endothelin A; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: congenital absence of the vas deferens; cystic fibrosis; genetic modifiers; male infertility; p.Phe508del mutation