Abstract
Purpose
To identify the genetic causes of multiple morphological abnormalities in sperm flagella (MMAF) and male infertility in patients from two unrelated Han Chinese families.
Methods
Whole-exome sequencing was conducted using blood samples from the two individuals with MMAF and male infertility. Hematoxylin and eosin staining and scanning electron microscopy were performed to evaluate sperm morphology. Ultrastructural and immunostaining analyses of the spermatozoa were performed. The HEK293T cells were used to confirm the pathogenicity of the variants.
Results
We identified two novel homozygous missense ARMC2 variants: c.314C > T: p.P105L and c.2227A > G: p.N743D. Both variants are absent or rare in the human population genome data and are predicted to be deleterious. In vitro experiments indicated that both ARMC2 variants caused a slightly increased protein expression. ARMC2-mutant spermatozoa showed multiple morphological abnormalities (bent, short, coiled, absent, and irregular) in the flagella. In addition, the spermatozoa of the patients revealed a frequent absence of the central pair complex and disrupted axonemal ultrastructure.
Conclusion
We identified two novel ARMC2 variants that caused male infertility and MMAF in Han Chinese patients. These findings expand the mutational spectrum of ARMC2 and provide insights into the complex causes and pathogenesis of MMAF.
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Data availability
The whole-exome sequencing data in this study have not been deposited in public repository because of privacy and ethical restrictions but are available from the corresponding author on reasonable request.
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Acknowledgements
The authors wish to sincerely thank all the families and individuals who participated in this study. The support from the technical platform and clinicians involved at the Jiangxi Maternal and Child Health Hospital and the Reproductive and Genetic Hospital of CITIC-Xiangya is gratefully acknowledged.
Funding
This work was supported by the National Natural Science Foundation of China (82101961 to CF.T.) and the outstanding Youth Foundation of Hunan Provincial Natural Science Foundation of China (2023JJ20080 to CF.T.).
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Zhao, S., Liu, Q., Su, L. et al. Identification of novel homozygous asthenoteratospermia-causing ARMC2 mutations associated with multiple morphological abnormalities of the sperm flagella. J Assist Reprod Genet 41, 1297–1306 (2024). https://doi.org/10.1007/s10815-024-03087-9
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DOI: https://doi.org/10.1007/s10815-024-03087-9