Mutations in non-muscle myosin 2A (NM 2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) that can include cataracts, glomerulosclerosis, macrothrombocytopenia, and deafness. 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, but male, and not female, mice are infertile. E1841K homozygous males have reduced testes size starting from three weeks after birth with defects in Sertoli-Sertoli and Sertoli-germ cell junctions, resulting in loss of blood-testis barrier integrity and premature germ cell loss into the epididymis. We found that mice conditionally ablated for NM 2A in Sertoli cells remain fertile and display none of the defects seen in E1841K homozygote males, suggesting that NM 2A is dispensable in Sertoli cells, and that the E1841K mutation interferes with spermatogenesis in a mode different from loss-of-function. Ongoing studies utilizing mice conditionally ablated for both NM 2A and NM 2B in Sertoli cells may help clarify whether mutant NM 2A interferes with normal NM 2B in a dominant negative fashion during the formation of mixed bipolar filaments. Together, these results identify a previously unreported consequence of NM 2A mutations in MYH9-RD mouse models and provide further insight into the role of NM 2A in Sertoli cells during germ cell maturation and postnatal testes development.
