Zhang Duo, Huang Wu-Jian, Chen Guo-Yong, Dong Li-Hong, Tang Ying, Zhang Hui, Li Qing-Qin, Mei Xiao-Yan, Wang Zhi-Hong, Lan Feng-Hua
Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.
Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.
Mol Hum Reprod. 2021 May 8;27(5). doi: 10.1093/molehr/gaab028.
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.
无头精子症综合征（ASS）是一种导致男性不育的罕见畸形精子症。先前的研究表明其起源于遗传。含Sad1和UNC84结构域蛋白5（SUN5）的变异是ASS的主要遗传病因；然而，其发病机制仍不清楚。在此，我们对10例无亲缘关系的ASS患者进行了全外显子组测序，在4例患者的SUN5基因中鉴定出2个纯合变异，即c.381delA[p.V128Sfs7*]和c.675C>A[p.Y225X]，以及1个复合变异，即c.88 C>T[p.R30X]和c.381 delA [p.V128Sfs7*]。c.381delA变异在先前的报道中已被确定为致病性变异，而c.675C>A和c.88 C>T是两个新的变异，它们可导致过早终止密码子（PTC）并导致SUN5缺失，也可能具有致病性。在携带SUN5无义突变的ASS患者中，SUN5 mRNA和蛋白水平极低。此外，在携带SUN5变异的ASS患者精子中，外致密纤维蛋白1（ODF1）和Nesprin3的分布发生了改变。免疫共沉淀分析表明，SUN5与ODF1、SUN5与Nesprin3以及ODF1与Nesprin3在转染的HEK293T细胞中相互作用。因此，我们提出SUN5、Nesprin3和ODF1可能通过在精子颈部的相互作用形成一个“三联体”结构。当基因变异导致SUN5缺失时，“三联体”结构消失，进而头尾连接变得脆弱，导致ASS的发生。
