Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Andrology. 2017 Sep;5(5):954-957. doi: 10.1111/andr.12407. Epub 2017 Aug 14.
Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing. In this study, we performed whole-exome sequencing in 18 unrelated CBAVD patients and identified two missense variants in two patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E). Both variants were predicted to be deleterious and highly conserved in silico. The p.C570Y variant is located in the G protein-coupled receptor (GPCR) proteolysis site domain, which is functionally necessary for autoproteolysis, while the p.K990E variant is in the N-terminal fragment that may regulate activity of the adhesion GPCR. We did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients. To the best of our knowledge, these are the first two ADGRG2 variants to be identified in Chinese CBAVD patients, which further validate the disease-causing role of ADGRG2 in this congenital defect.
先天性双侧输精管缺如（CBAVD）是全球梗阻性无精子症和男性不育的重要原因。囊性纤维化跨膜电导调节因子（CFTR）突变是主要的致病原因，尽管有一部分病例仍未得到解释。最近，黏附 G 蛋白偶联受体 G2（ADGRG2）基因被确定为 CBAVD 的一个新的致病基因。我们在中国人 CBAVD 患者中进行了一项单人群复制研究，以验证其在 CBAVD 发病中的作用。在这项研究中，我们对 18 名无关联的 CBAVD 患者进行了全外显子组测序，在两名患者中发现了两个错义变异（c.G1709A，p.C570Y；和 c.A2968G，p.K990E）。这两种变异均被预测为有害且在计算机中高度保守。p.C570Y 变异位于 G 蛋白偶联受体（GPCR）蛋白水解位点结构域，该结构域对自水解功能至关重要，而 p.K990E 变异位于可能调节黏附 GPCR 活性的 N 端片段。我们没有发现任何潜在的致病性 CFTR 变异，这意味着 ADGRG2 变异是这些患者的遗传原因。据我们所知，这些是在中国 CBAVD 患者中首次发现的两种 ADGRG2 变异，进一步验证了 ADGRG2 在这种先天性缺陷中的致病作用。
