SEPT12 mutations cause male infertility with defective sperm annulus
SEPT12 mutations cause male infertility with defective sperm annulus
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DOI：
10.1002/humu.22028
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发表时间：
2012-04-01
期刊：
影响因子：
3.9
通讯作者：
Kuo, Pao-Lin
中科院分区：
文献类型：
--
作者：
Kuo, Yung-Che;Lin, Ying-Hung;Kuo, Pao-Lin
septin是GTPase超家族的成员，涉及多种细胞功能，包括细胞分裂和形态发生。Septin 12 （SEPT12）是睾丸特异性基因，对男性生殖细胞的终末分化至关重要。我们报道了两个错义SEPT12突变的鉴定，c.266C>T/p。Thr89Met和c.589G>A/p。在不育男性中。这两种突变都位于GTPase结构域内，并可能改变蛋白质结构。p.Thr89Met突变显著降低了鸟苷-5'-三磷酸（GTP）水解活性，p.Asp197Asn突变（SEPT12D197N）干扰了GTP的结合。两种突变体SEPT12蛋白以剂量依赖的方式限制了野生型SEPT12的丝形成。携带SEPT12D197N的患者表现为少弱性精子症，而携带SEPT12T89M的患者表现为弱弱性精子症。SEPT12D197N患者的特征性精子病理包括畸形精子环带弯尾和异常精子环中SEPT12缺失。我们的发现表明，SEPT12的功能缺失突变通过扰乱septin丝的形成破坏了精子的结构完整性。[j] .中国农业科学，2012。(c) 2012 Wiley期刊有限公司
Septins are members of the GTPase superfamily, which has been implicated in diverse cellular functions including cytokinesis and morphogenesis. Septin 12 (SEPT12) is a testis-specific gene critical for the terminal differentiation of male germ cells. We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTPase domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation significantly reduced guanosine-5'-triphosphate (GTP) hydrolytic activity, and the p.Asp197Asn mutation (SEPT12D197N) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild-type SEPT12 in a dose-dependent manner. The patient carrying SEPT12D197N presented with oligoasthenozoospermia, whereas the SEPT12T89M patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12D197N patient included defective annulus with bent tail and loss of SEPT12 from the annulus of abnormal sperm. Our finding suggests loss-of-function mutations in SEPT12 disrupted sperm structural integrity by perturbing septin filament formation. Hum Mutat 33:710719, 2012. (c) 2012 Wiley Periodicals, Inc.