Sharma H, Mavuduru R S, Singh S K, Prasad R
Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Department of Urology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23.
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.
囊性纤维化（CF）在印度人群中通常被认为是一种罕见疾病。两项研究报告了先天性输精管缺如（CAVD）的印度男性中囊性纤维化跨膜传导调节因子（CFTR）基因突变的频率，然而，关于CFTR基因突变谱的数据仍然缺乏。因此，本研究旨在确定CFTR基因突变谱，并调查CF基因修饰因子与不育印度男性中CAVD外显率的关联。对总共60例连续诊断为CAVD的不育男性进行了CFTR基因分析，结果显示有13种不同的CFTR基因突变和1种导致异常剪接的内含子变异。p.Phe508del（n = 16）和p.Arg117His（n = 4）是所鉴定出的最常见的严重形式的CFTR突变。被认为是CFTR突变轻度形式的IVS8-T5等位基因，其等位基因频率为28.3%。在我们的患者队列中，CFTR基因还鉴定出了8种新突变。值得注意的是，CFTR基因突变谱具有异质性，外显子4和外显子11是热点区域。此外，我们还发现CF基因修饰因子，即转化生长因子（TGF）-β1和A型内皮素受体（EDNRA）基因与CAVD表型有关联。这些发现具有相当大的临床意义，因为因CAVD导致不育的男性可以决定使用辅助生殖技术。CAVD男性的子女有携带CFTR突变的风险；因此，遗传咨询对这类患者来说是关键步骤。特别提及像印度这样的发展中国家，在那里进行全基因测序不可行，我们的研究结果将使CFTR基因的筛查程序更简单且更具成本效益，因为我们已经确定了CFTR基因在患有CAVD的印度男性中更容易发生突变的热点区域。此外，这是来自印度人群的第一项研究，旨在调查CF基因修饰因子与CAVD表型外显率的关联。观察到的基因修饰因子TGF-β1和EDNRA与CAVD外显率的关联进一步支持了它们参与输精管的发生过程。
