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 ten unrelated ASS and identified two homozygous variants, c.381delA[p.V128Sfs7*] and c.675C>A[p.Y225X], and one compound variant, c.88 C > T[p.R30X] and c.381 delA [p.V128Sfs7*], in SUN5 in four 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 Variant引起的脑性精子综合征的发病机制。

脑性精子症候群（ASS）是一种罕见的畸形精子症，可导致男性不育。先前的工作提出了遗传起源。含有5（SUN5）的Sad1和UNC84结构域的变异是ASS的主要遗传原因，但其发病机理仍不清楚。在这里，我们在十个无关的ASS中进行了全外显子组测序，并确定了两个纯合变异体c.381delA [p.V128Sfs7 *]和c.675C> A [p.Y225X]，以及一个化合物变异体c.88 C> T [p.R30X]和c.381 delA [p.V128Sfs7 *]，在SUN5中有4位患者。c.381delA变体在先前的报告中已被确认为致病菌，而c.675C> A和c.88 C> T是两个新的变体，它们可能导致过早终止密码子（PTC），并导致SUN5的丢失，并且也可能是致病的。在具有SUN5无意义突变的ASS患者中，SUN5 mRNA和蛋白质的含量非常低。此外，在患有SUN5变异的ASS患者的精子中，外部致密纤维蛋白1（ODF1）和Nesprin3的分布发生了改变。免疫共沉淀分析表明，在转染的HEK293T细胞中，SUN5和ODF1，SUN5和Nesprin3以及ODF1和Nesprin3相互作用。因此，我们建议SUN5，Nesprin3和ODF1可以通过精子颈部的相互作用形成“三胞胎”结构。当基因变异导致SUN5丢失时，“三胞胎”结构消失，然后头尾连接变得脆弱，导致ASS的发生。免疫共沉淀分析表明，在转染的HEK293T细胞中，SUN5和ODF1，SUN5和Nesprin3以及ODF1和Nesprin3相互作用。因此，我们建议SUN5，Nesprin3和ODF1可以通过精子颈部的相互作用形成“三胞胎”结构。当基因变异导致SUN5丢失时，“三胞胎”结构消失，然后头尾连接变得脆弱，导致ASS的发生。免疫共沉淀分析表明，在转染的HEK293T细胞中，SUN5和ODF1，SUN5和Nesprin3以及ODF1和Nesprin3相互作用。因此，我们建议SUN5，Nesprin3和ODF1可以通过精子颈部的相互作用形成“三胞胎”结构。当基因变异导致SUN5丢失时，“三胞胎”结构消失，然后头尾连接变得脆弱，导致ASS的发生。