Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China.
Elife. 2024 Nov 6;13:RP96755. doi: 10.7554/eLife.96755.
Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients' sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with variants and KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.
轴丝蛋白复合物，包括外臂和内臂动力蛋白（ODA/IDA），是精子鞭毛的高度有序结构，驱动精子运动。几种轴丝蛋白的缺乏与男性不育有关，其特征是弱精症或畸形精子症。动力蛋白轴丝重链 3（DNAH3）位于 IDA 中，在睾丸中高度表达。然而，DNAH3 与男性不育之间的关系仍不清楚。在此，我们通过全外显子组测序（WES）在 4 名具有弱精畸形症的汉族非育男性中鉴定出 DNAH3 基因的双等位基因突变。这些变异导致患者精子鞭毛中 DNAH3 表达不足。重要的是，患者表现出异常的精子鞭毛形态，鞭毛超微结构严重受损。有趣的是，DNAH3 敲除（KO）雄性小鼠也不育，尤其是精子运动严重减少，同时伴有 IDA 和线粒体结构异常。从机制上讲，非功能性 DNAH3 表达导致患者和 KO 小鼠精子鞭毛中与 IDA 相关的蛋白表达减少，包括 DNAH1、DNAH6 和 DNALI1，这些蛋白的缺失已涉及到精子运动的破坏。此外，携带 DNAH3 变异的患者和 DNAH3 KO 小鼠的不育可以通过胞浆内单精子注射（ICSI）治疗得到挽救。我们的研究结果表明，DNAH3 是弱精畸形症的一个新的致病基因，可能进一步有助于男性不育的诊断、遗传咨询和预后。
