A variant in sperm‐specific glycolytic enzyme enolase 4 (ENO4) causes human male infertility

Abstract

BackgroundAlthough defects in sperm morphology and physiology lead to male infertility, in many instances, the exact disruption of molecular pathways in a given patient is often unknown. The glycolytic pathway is an essential process to supply energy in sperm cell motility. Enolase 4 (ENO4) is crucial for the glycolytic process, which provides the energy for sperm cells in motility. ENO4 is located in the sperm principal piece and is essential for the motility and organization of the sperm flagellum. In the present study, we characterized a family with asthenozoospermia and abnormal sperm morphology as a result of a variant in the enolase 4 (ENO4) gene.MethodsComputer‐assisted semen analysis, papanicolaou smear staining and scanning electron microscopy were used to examine sperm motility and morphology for semen analysis in patients. For genetic analysis, whole‐exome sequencing followed by Sanger sequencing was performed.ResultsTwo brothers in a consanguineous family were being clinically investigated for sperm motility and morphology issues. Genetic analysis by whole‐exome sequencing revealed a homozygous variant [c.293A>G, p.(Lys98Arg)] in the ENO4 gene that segregated with infertility in the family, shared by affected but not controls.ConclusionsIn view of the association of asthenozoospermia and abnormal sperm morphology in Eno4 knockout mice, we consider this to be the first report describing the involvement of ENO4 gene in human male infertility. We also explore the possible involvement of another variant in explaining other phenotypic features in this family.

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum

“…While we did find modest genetic correlation between female infertility and age at first sexual intercourse (-18.8%), indicating that the latter captures some shared biology with fertility, our meta-analyses did not replicate the associations of infertility proxy variables with putative behavioural loci for risk-taking 85,86 or educational attainment 85,[87][88][89] . Instead, we nominate genes with putative roles in both male and female gonads, such as TRHR for ovarian insufficiency 39,40 and ENO4 for sperm motility 44 .…”

“…INHBB encodes the beta subunit of inhibin B, which regulates hypothalamic, pituitary, and gonadal hormone secretion 42 , and ovarian follicle and oocyte development 43 . Finally, an intronic variant in ENO4, which is expressed in the testis and may play a role in sperm motility 44 , is associated with male infertility (rs139862664, OR=0.388 (0.277-0.543)). Male mice with ENO4 knockouts display infertility, abnormal sperm morphology and physiology, and decreased testis weight, among other altered male reproductive tract phenotypes 45 .…”