Abstract

Asthenozoospermia is the most common cause of male infertility. Dynein protein arms play a crucial role in the motility of both the cilia and flagella, and defects in these proteins generally impair the axoneme structure and cause primary ciliary dyskinesia. But relatively little is known about the influence of dynein protein arm defects on sperm flagella function. Here, we recruited 85 infertile patients with idiopathic asthenozoospermia and identified bi-allelic mutations in DNAH7 (NM_018897.3) from three patients using whole-exome sequencing. These variants are rare, highly pathogenic, and very conserved. The spermatozoa from the patients with DNAH7 bi-allelic mutations showed specific losses in the inner dynein arms. The expression of DNAH7 in the spermatozoa from the DNAH7-defective patients was significantly decreased, but these patients were able to have their children via intra-cytoplasmic sperm injection treatment. Our study is the first to demonstrate that bi-allelic mutations in DNAH7 may impair the integrality of axoneme structure, affect sperm motility, and cause asthenozoospermia in humans. These findings may extend the spectrum of etiological genes and provide new clues for the diagnosis and treatment of patients with asthenozoospermia.

中文翻译：

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DNAH7的双等位基因突变通过损害轴突结构的完整性导致弱精子症

摘要

弱精子症是男性不育的最常见原因。动力蛋白臂在纤毛和鞭毛的运动中起着至关重要的作用，这些蛋白质的缺陷通常会损害轴丝结构并导致原发性纤毛运动障碍。但关于动力蛋白臂缺陷对精子鞭毛功能的影响知之甚少。在这里，我们招募了 85 名患有特发性弱精子症的不育患者，并使用全外显子组测序从 3 名患者中鉴定出DNAH7 (NM_018897.3) 的双等位基因突变。这些变异是罕见的、高致病性的并且非常保守。DNAH7双等位基因突变患者的精子显示出内部动力蛋白臂的特定损失。DNAH7 在精子中的表达DNAH7缺陷的患者明显减少，但这些患者能够通过胞浆内精子注射治疗生下他们的孩子。我们的研究首次证明DNAH7中的双等位基因突变可能会损害轴丝结构的完整性，影响精子活力，并导致人类弱精子症。这些发现可能会扩展病因基因谱，为弱精子症患者的诊治提供新的线索。