Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in Chinese
Homozygous DNAH1 frameshift mutation causes multiple morphological anomalies of the sperm flagella in Chinese
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纯合DNAH1移码突变导致中国人精子鞭毛多种形态异常
DOI：
10.1111/cge.12857
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发表时间：
2017-02-01
影响因子：
3.5
通讯作者：
Gao, Z.
中科院分区：
文献类型：
--
作者：
Wang, X.;Jin, H.;Gao, Z.
本研究旨在探讨鞭毛多种形态异常（MMAF）的遗传发病机制，这是一种导致男性不育的遗传异质性疾病。招募了 9 名由 MMAF 引起的严重弱精子症患者。进行全基因组测序和桑格测序，我们发现这 9 名患者中有 4 名在动力蛋白轴丝重链 1 (DNAH1) 基因的外显子 73 中受到相同的纯合移码突变 c.11726_11727delCT (p.[Pro3909ArgfsTer33]) 的影响。先证者1的父母和兄弟姐妹均被鉴定为杂合子携带者。这种突变与之前报道的与 MMAF 相关的 DNAH1 突变不同，并且仅影响东亚群体。此外，尽管精子中表达了DNAH1 mRNA，但通过蛋白质印迹或免疫荧光染色无法在精子中检测到变异DNAH1蛋白。扫描电子显微镜和透射电子显微镜分析显示携带这种遗传变异的患者精子鞭毛形态和超微结构存在异常。总之，我们的结果增加了对 MMAF 遗传病因的认识，并进一步证实了基因筛查在 MMAF 诊断中的有效性。
This study aimed to investigate the genetic pathogeny of multiple morphological anomalies of the flagella (MMAF), which is a genetically heterogeneous disorder leading to male infertility. Nine patients with severe asthenozoospermia caused by MMAF were recruited. Whole genome sequencing and Sanger sequencing were performed, and we found that four of the nine patients were affected by the same homozygous frameshift mutation c.11726_11727delCT (p.[Pro3909ArgfsTer33]) in exon 73 of dynein axonemal heavy chain 1 ( DNAH1 ) gene. The parents and the sibling of proband 1 were all identified as heterozygous carriers. This mutation was distinct from previously reported DNAH1 mutations associated with MMAF and only affected the East Asian group. Furthermore, the variant DNAH1 protein could not be detected in spermatozoa by Western blot or immunofluorescence staining although DNAH1 mRNA was expressed in the spermatozoa. Scanning electron microscopy and transmission electron microscopy analysis showed the anomalies in sperm flagella morphology and ultrastructure in patients carrying this genetic variant. In conclusion, our results add to knowledge of the genetic pathogeny of MMAF and further confirmed the effectiveness of genetic screening in the diagnosis of MMAF.