EIF4G1 is a novel candidate gene associated with severe asthenozoospermia

Abstract

Background Asthenozoospermia (AZS), also known as asthenospermia, is characterized by reduced motility of ejaculated spermatozoa and is detected in more than 40% of infertile patients. Because the proportion of progressive spermatozoa in severe AZS is <1%, severe AZS is an urgent challenge in reproductive medicine. Several genes have been reported to be relevant to severe asthenospermia. However, these gene mutations are found only in sporadic cases and can explain only a small fraction of severe AZS, so additional genetic pathogenies need to be explored. Methods and results By screening the variant genes in a patient with severe AZS using whole exome sequencing, we identified biallelic mutations c.2521C>T: p.(Pro841Ser) (NC_000003.11: g.184043412C>T) in exon13 and c.2957C>G: p.(Ala986Gly) (NC_000003.11: g.184045117C>G) in exon17 in the eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1, RefSeq: NM_004953.4, OMIM: 600495) of the patient. Both of the mutation sites are rare and potentially deleterious. Transmission electron microscopy analysis showed a disrupted axonemal structure with mitochondrial sheath defects. The EIF4G1 protein level was extremely low, and the mitochondrial marker cytochrome c oxidase subunit 4I1 (COXIV, OMIM: 123864) and mitochondrially encoded ATP synthase 6 (ATP6, OMIM: 516060) protein levels were also decreased in the patient's spermatozoa as revealed by WB and IF analysis. This infertility associated with this condition was overcome by intracytoplasmic sperm injections, as his wife became pregnant successfully. Conclusion Our experimental findings indicate that the EIF4G1 gene is a novel candidate gene that may be relevant to severe AZS.

Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia

“…QRT-PCR experiment of DNAH9-mRNA and immunofluorescence staining experiment of DNAH9-protein in sperm were performed in accordance with previous study [ 9 , 21 ]. The primary anti-DNAH9 was Anti-Dynein heavy chain antibody (ab133968, ABCAM).…”

“…DNA from whole peripheral blood was used to perform WES and bioinformatic analysis. And the protocols were in accordance with previous research [ 9 , 21 ]. Sanger sequencing was performed to verify the identified variants and parental origins.…”

“…Sperm sample was prepared and treated as described previously [ 9 , 21 ]. Subsequently, transmission electron microscopy (TEM, TECNAI-10, 80 kV, Philips, Holland) was used to observe ultrastructures of sperm tail.…”

“…Previous studies have presented that genetic disorders might be related to severe asthenospermia. Sha et al has found that EIF4G1 (OMIM: 600495) was a candidate gene of severe asthenospermia in one patient, whose sperm was revealed with mitochondrial sheath defects [ 9 ]. Similarly, Xu et al identified a homozygous SPAG17 (OMIM: 616554) mutation was associated with severe asthenozoospermia in a familial twins [ 10 ].…”

Novel Variants in DNAH9 Lead to Nonsyndromic Severe Asthenozoospermia

“…Previous studies have presented that genetic disorders might be related to severe asthenospermia. Sha et al has found that EIF4G1 (OMIM: 600495) was a candidate gene of severe asthenospermia in one patient, whose sperm was revealed with mitochondrial sheath defects [9]. Similarly, Xu et al identi ed a homozygous SPAG17 (OMIM: 616554) mutation was associated with severe asthenozoospermia in a familial twins [10].…”