Asthenozoospermia, defined by the absence or reduction of sperm motility, constitutes the most frequent cause of human male infertility. This pathological condition is caused by morphological and/or functional defects of the sperm flagellum, which preclude proper sperm progression. While in the last decade many causal genes were identified for asthenozoospermia associated with severe sperm flagellar defects, the causes of purely functional asthenozoospermia are still poorly defined. We describe here the case of an infertile man, displaying asthenozoospermia without major morphological flagellar anomalies and carrying a homozygous splicing mutation in SLC9C1 (sNHE), which we identified by whole‐exome sequencing. SLC9C1 encodes a sperm‐specific sodium/proton exchanger, which in mouse regulates pH homeostasis and interacts with the soluble adenylyl cyclase (sAC), a key regulator of the signalling pathways involved in sperm motility and capacitation. We demonstrate by means of RT‐PCR, immunodetection and immunofluorescence assays on patient's semen samples that the homozygous splicing mutation (c.2748 + 2 T > C) leads to in‐frame exon skipping resulting in a deletion in the cyclic nucleotide‐binding domain of the protein. Our work shows that in human, similar to mouse, SLC9C1 is required for sperm motility. Overall, we establish a homozygous truncating mutation in SLC9C1 as a novel cause of human asthenozoospermia and infertility.

中文翻译：

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钠/质子交换剂 SLC9C1 (sNHE) 对人类精子活力和生育能力至关重要

由精子活力缺失或减少定义的弱精子症是人类男性不育的最常见原因。这种病理状况是由精子鞭毛的形态和/或功能缺陷引起的，这妨碍了精子的正常发展。虽然在过去的十年中，许多与严重精子鞭毛缺陷相关的弱精子症的致病基因被鉴定出来，但纯粹功能性弱精子症的原因仍然不清楚。我们在此描述了一个不育男性的病例，其表现出无主要形态鞭毛异常的弱精子症，并在SLC9C1 ( sNHE )中携带纯合剪接突变，我们通过全外显子组测序对其进行了鉴定。SLC9C1编码精子特异性钠/质子交换剂，在小鼠体内调节 pH 稳态并与可溶性腺苷酸环化酶 (sAC) 相互作用，后者是参与精子运动和获能的信号通路的关键调节剂。我们通过对患者精液样本的 RT-PCR、免疫检测和免疫荧光测定证明，纯合剪接突变 ( c.2748 + 2 T > C ) 导致框内外显子跳跃导致环核苷酸结合域缺失的蛋白质。我们的工作表明，在人类中，与小鼠相似，SLC9C1 是精子活力所必需的。总的来说，我们在SLC9C1中建立了一个纯合截断突变作为人类弱精子症和不育症的新原因。