DNAH3 缺乏会导致鞭毛内动力蛋白臂缺失以及人类和小鼠雄性不育。

IF 6.4 1区 生物学 Q1 BIOLOGY eLife Pub Date : 2024-11-06 DOI:10.7554/eLife.96755
Xiang Wang, Gan Shen, Yihong Yang, Chuan Jiang, Tiechao Ruan, Xue Yang, Liangchai Zhuo, Yingteng Zhang, Yangdi Ou, Xinya Zhao, Shunhua Long, Xiangrong Tang, Tingting Lin, Ying Shen
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引用次数: 0

摘要

轴丝蛋白复合物(包括外侧和内侧动力蛋白臂(ODA/IDA))是精子鞭毛的高度有序结构,可驱动精子运动。几种轴突蛋白的缺乏与男性不育有关,表现为无精子症或少精子症。Dynein轴突蛋白重链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)在四名患有无精子症的无血缘关系汉族不育男性中发现了DNAH3的双拷贝变体。这些变异导致患者精子鞭毛中DNAH3表达不足。重要的是,这些患者的精子鞭毛形态异常,鞭毛超微结构受到严重破坏。耐人寻味的是,Dnah3基因敲除(KO)雄性小鼠也不育,尤其是精子运动能力严重下降,IDA和线粒体结构异常。从机理上讲,DNAH3的无功能表达导致患者和KO小鼠精子鞭毛中IDA相关蛋白的表达减少,包括DNAH1、DNAH6和DNALI1,这些蛋白的缺失参与了精子活力的破坏。此外,DNAH3变体患者和Dnah3 KO小鼠的不育症可以通过卵胞浆内单精子注射(ICSI)治疗得到挽救。我们的研究结果表明,DNAH3是无精子症的一个新的致病基因,可进一步促进男性不育症的诊断、遗传咨询和预后。
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DNAH3 deficiency causes flagellar inner dynein arm loss and male infertility in humans and mice.

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 DNAH3 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, Dnah3 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 DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

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来源期刊
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
期刊最新文献
Host-derived Lactobacillus plantarum alleviates hyperuricemia by improving gut microbial community and hydrolase-mediated degradation of purine nucleosides. Functional implications of the exon 9 splice insert in GluK1 kainate receptors. Single-cell multiomics analysis of chronic myeloid leukemia links cellular heterogeneity to therapy response. DNAH3 deficiency causes flagellar inner dynein arm loss and male infertility in humans and mice. Predicting drug resistance.
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