Acephalic spermatozoa syndrome (ASS) is a rare teratozoospermia that leads to male infertility. Previous work suggested a genetic origin. Variants of Sad1 and UNC84 domain containing 5 (SUN5) are the main genetic cause of ASS; however, its pathogenesis remains unclear. Here, we performed whole-exome sequencing in 10 unrelated ASS and identified 2 homozygous variants, c.381delA[p.V128Sfs7*] and c.675C>A[p.Y225X], and 1 compound variant, c.88 C > T[p.R30X] and c.381 delA [p.V128Sfs7*], in SUN5 in 4 patients. The c.381delA variant had been identified as pathogenic in previous reports, while c.675C>A and c.88 C > T were two novel variants which could lead to a premature termination codon (PTC) and resulted in loss of SUN5, and may also be pathogenic. SUN5 mRNA and protein were present at very low levels in ASS patients with SUN5 nonsense mutation. Furthermore, the distribution of outer dense fiber protein 1 (ODF1) and Nesprin3 was altered in sperm of ASS patients with SUN5 variants. The co-immunoprecipitation analysis indicated that SUN5 and ODF1, SUN5 and Nesprin3, and ODF1 and Nesprin3 interacted with each other in transfected HEK293T cells. Thus, we propose that SUN5, Nesprin3, and ODF1 may form a ‘triplet’ structure through interactions at neck of sperm. When gene variants resulted in a loss of SUN5, the ‘triplet’ structure disappears and then the head-tail junction becomes fragile, leading to the occurrence of ASS.

中文翻译：

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SUN5变异引起的头侧精子综合征的发病机制

无头精子综合征（ASS）是一种罕见的畸形精子症，可导致男性不育。以前的工作表明遗传起源。含有5（SUN5）的Sad1和UNC84结构域的变异是ASS的主要遗传原因；然而，其发病机制仍不清楚。在这里，我们在 10 个不相关的 ASS 中进行了全外显子组测序，并鉴定了 2 个纯合变体 c.381delA[p.V128Sfs7*] 和 c.675C>A[p.Y225X]，以及 1 个复合变体 c.88 C>。T[p.R30X] 和 c.381 delA [p.V128Sfs7*]，在 SUN5 中 4 名患者。c.381delA 变体在之前的报告中已被确定为致病性，而 c.675C>A 和 c.88C>A T 是两个新的变体，它们可能导致提前终止密码子 (PTC) 并导致 SUN5 的丢失，并且也可能是致病的。SUN5 mRNA 和蛋白质在具有 SUN5 无义突变的 ASS 患者中以非常低的水平存在。此外，外层致密纤维蛋白 1 (ODF1) 和 Nesprin3 在具有 SUN5 变异的 ASS 患者的精子中的分布发生了改变。共免疫沉淀分析表明SUN5和ODF1、SUN5和Nesprin3、ODF1和Nesprin3在转染的HEK293T细胞中相互作用。因此，我们提出 SUN5、Nesprin3 和 ODF1 可能通过精子颈部的相互作用形成“三联体”结构。当基因变异导致 SUN5 丢失时，“三联体”结构消失，然后头尾连接变得脆弱，导致 ASS 的发生。共免疫沉淀分析表明SUN5和ODF1、SUN5和Nesprin3、ODF1和Nesprin3在转染的HEK293T细胞中相互作用。因此，我们提出 SUN5、Nesprin3 和 ODF1 可能通过精子颈部的相互作用形成“三联体”结构。当基因变异导致 SUN5 丢失时，“三联体”结构消失，然后头尾连接变得脆弱，导致 ASS 的发生。共免疫沉淀分析表明SUN5和ODF1、SUN5和Nesprin3、ODF1和Nesprin3在转染的HEK293T细胞中相互作用。因此，我们提出 SUN5、Nesprin3 和 ODF1 可能通过精子颈部的相互作用形成“三联体”结构。当基因变异导致 SUN5 丢失时，“三联体”结构消失，然后头尾连接变得脆弱，导致 ASS 的发生。