Mutations in non-muscle myosin 2A (NM2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) in humans that can include macrothrombocytopenia, glomerulosclerosis, deafness, and cataracts. We previously created mouse models of the three mutations most frequently found in humans: R702C, D1424N, and E1841K. While homozygous R702C and D1424N mutations are embryonic lethal, we found homozygous mutant E1841K mice to be viable. However the homozygous male, but not female, mice were infertile. Here, we report that these mice have reduced testis size and defects in actin-associated junctions in Sertoli cells, resulting in inability to form the blood-testis barrier and premature germ cell loss. Moreover, compound double heterozygous (R702C/E1841K and D1424/E1841K) males show the same abnormalities in testes as E1841K homozygous males. Conditional ablation of either NM2A or NM2B alone in Sertoli cells has no effect on fertility and testis size, however deletion of both NM2A and NM2B in Sertoli cells results in infertility. Isolation of mutant E1841K Sertoli cells reveals decreased NM2A and F-actin colocalization and thicker NM2A filaments. Furthermore, A^E1841K/A^E1841K and double knockout Sertoli cells demonstrate microtubule disorganization and increased tubulin acetylation, suggesting defects in the microtubule cytoskeleton. Together, these results demonstrate that NM2A and 2B paralogs play redundant roles in Sertoli cells and are essential for testes development and normal fertility.

非肌肉肌球蛋白 2A (NM2A) 中的突变包括广泛的异常，统称为人类 MYH9 相关疾病 (MYH9-RD)，其中可能包括巨血小板减少症、肾小球硬化症、耳聋和白内障。我们之前创建了人类最常见的三种突变的小鼠模型：R702C、D1424N 和 E1841K。虽然纯合 R702C 和 D1424N 突变是胚胎致死的，但我们发现纯合突变 E1841K 小鼠是可行的。然而，纯合雄性而非雌性小鼠是不育的。在这里，我们报告说，这些小鼠的睾丸大小减小，支持细胞中肌动蛋白相关连接的缺陷，导致无法形成血睾丸屏障和过早的生殖细胞丢失。而且，复合双杂合子（R702C/E1841K 和 D1424/E1841K）雄性在睾丸中表现出与 E1841K 纯合子雄性相同的异常。在支持细胞中单独去除 NM2A 或 NM2B 的条件消融对生育力和睾丸大小没有影响，但是在支持细胞中同时删除 NM2A 和 NM2B 会导致不育。突变 E1841K 支持细胞的分离显示 NM2A 和 F-肌动蛋白共定位减少和 NM2A 细丝变粗。此外，一个^E1841K /A ^E1841K和双敲除支持细胞表现出微管解体和微管蛋白乙酰化增加，表明微管细胞骨架存在缺陷。总之，这些结果表明 NM2A 和 2B 旁系同源物在支持细胞中起着多余的作用，对睾丸发育和正常生育能力至关重要。