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Abstract
Background The information of ZMYND15 in human reproduction is very limited, resulting in the unclear link between ZMYND15 variants and male infertility.
Methods Whole exome sequencing and Sanger sequencing to identify the potential pathogenic variation of ZMYND15 in infertile men, Papanicolaou staining and electron microscopy to investigate the spermatozoa morphology, western blotting and immunofluorescence staining to confirm the pathogenicity of the identified variants, and proteomic analysis and coimmunoprecipitation to clarify the potential molecular mechanism.
Results A total of 31 ZMYND15 variants were identified in 227 infertile patients. Three deleterious biallelic variants, including a novel compound heterozygous variant of c.1105delG (p.A369Qfs*15) and c.1853T>C (p.F618S), a new homozygous splicing mutation of c.1297+5G>A and a reported homozygous nonsense mutation of c.1209T>A (p.Y403*), were detected in three affected individuals with oligoasthenoteratozoospermia, showing a biallelic pathogenic mutation frequency of 1.3% (3/227). No biallelic pathogenic mutation was found in 692 fertile men. Morphology analysis showed abnormalities in sperm morphology in the patients harbouring ZMYND15 mutations. Western blotting and immunofluorescence staining confirmed the nearly absent ZMYND15 expression in the sperm of the patients. Mechanistically, ZMYND15 might regulate spermatogenesis by interacting with key molecules involved in sperm development, such as DPY19L2, AKAP4 and FSIP2, and might also mediate the expression of the autophagy-associated protein SPATA33 to maintain sperm individualisation and unnecessary cytoplasm removal.
Conclusion Our findings broaden the variant and phenotype spectrum of ZMYND15 in male infertility, and reveal the potential signalling pathway of ZMYND15 regulating spermatogenesis, finally confirming the essential role of ZMYND15 in human fertility.
- reproductive medicine
- genetics
Data availability statement
Data are available on reasonable request.
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Data availability statement
Data are available on reasonable request.
Footnotes
YW and XW are joint first authors.
YW and XW contributed equally.
Contributors As guarantor, YS designed and supervised the study experiments. YY collected data and conducted the clinical assessments. JL performed WES and analysed its data. XW performed electron microscopy evaluation and proteomic analysis. YW was responsible for the immunofluorescence staining and Co-IP, RZ carried out western blotting, and SD cultured cells and conducted the transfection experiment. YW wrote the manuscript. All authors revised and approved the article.
Funding This work was supported by the West China Second University Hospital of Sichuan University (No. KS369) and the Key Research and Development Program of Sichuan Province (2021YFS0094).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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