SPEM2 deficiency disrupts spermiation leading to oligoasthenoteratozoospermia and male infertility

Oligoasthenoteratozoospermia (OAT) is a prevalent phenotype among infertile males, yet its underlying genetic etiology remains largely undefined. In this study, we found Spem2 deficiency did not affect the development of spermatogenic cells or the eventual generation of elongated spermatids within the testis, but affected the normal formation of residual bodies during the late stage of spermiation, which led to incomplete cytoplasmic removal of spermatids, abnormal sperm release and caused OAT. Affected sperm exhibited severely bent heads, cytoplasmic remnants encasing the head, and multiple sperm gathered. We further found SPEM2 may be involved in maintaining spermiation and cell polarity through interactions with cell polar molecules VANGL2, PRICKLE3 and DVL3. In vitro experiments showed that the transmembrane region of SPEM2 was its key functional domain and the binding domain for interactions between SPEM2 and VANGL2. Importantly, Spem2-deficient sperm enabled successful fertilization via ICSI. Three novel SPEM2 heterozygous pathogenic variants were identified in four OAT patients by the whole-exome sequencing. Our findings revealed key roles of SPEM2 in spermiation, explored the potential pathogenesis of male infertility caused by SPEM2 deficiency, and provided essential information for genetic and reproductive counseling for such patients.