We have generated a mouse line with a mutation frequently found in human MYH9 related disease, E1841K. In addition to modeling the defects seen in humans with MYH9-related disease, male, but not female, mice homozygous for the mutation are sterile. The male mice demonstrate severe defects in sperm development. Histological analyses of homozygous testis reveal that spermatocytes arrest at the elongated spermatid stage and aberrant spermatids slough off into the lumen. Some seminiferous tubules contain vacuoles, have a large lumen and often lack germ cells, while others appear normal but completely fail to develop a lumen. Electron micrographs uncover an abnormal flattening and extension of the acrosomal vesicle, which appears to lead to the abnormal elongation of spermatids. TUNEL assays of homozygous testis show an increase in apoptotic germ cells when compared to wild type. Caudal epididymis sections have only a few malformed spermatozoa that are rarely motile. Heterozygous mice show similar, albeit less severe, defects and are fertile. Sperm counts obtained from the caudal epididymis confirm a pronounced decrease in mature sperm in homozygous mice, while the heterozygous mice show a modest decrease when compared to wild type. Collectively, these observations suggest a previously unknown, critical role for NMII-A in spermatogenesis and male fertility.
