Abstract
Purpose
To identify the genetic causes for acephalic spermatozoa syndrome.
Methods
Whole-exome sequencing was performed on the proband from a non-consanguineous to identify pathogenic mutations for acephalic spermatozoa syndrome. Quantitative real-time polymerase chain reaction and whole genome sequencing were subjected to detect deletion. The functional effect of the identified splicing mutation was investigated by minigene assay. Western blot and immunofluorescence were performed to detect the expression level and localization of mutant TSGA10 protein.
Results
Here, we identified a novel heterozygous splicing mutation in TSGA10 (NM_025244: c.1108-1G > T), while we confirmed that there was a de novo large deletion in the proband. The splicing mutation led to the skipping of the exon15 of TSGA10, which resulted in a truncated protein (p. A370Efs*293). Therefore, we speculated that the splicing mutation might affect transcription and translation without the dosage compensation of a normal allele, which possesses a large deletion including intact TSGA10. Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype.
Conclusion
Our finding expands the spectrum of pathogenic TSGA10 mutations that are responsible for ASS and male infertility. It is also important to remind us of paying attention to the compound heterozygous deletion in patients from non-consanguineous families, so that we can provide more precise genetic counseling for patients.
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Data availability
The data underlying this article are available in the article.
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Acknowledgements
We would like to sincerely thank the patient and his family for participation.
Funding
National Natural Science Foundation of China (82071701 to F. Z.; 81792641 to F. W.), Natural Science Foundation of Anhui Province (1908085J28 to F. Z.), Key R&D program of Anhui Province (201904a07020050 to F. Z.), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310002), and Scientific Research Foundation of the Institute for Translational Medicine of Anhui Province (SRFITMAP 2017zhyx29 and ZHYX2020A001) supported this study.
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F.Z., Y.C., and F.W. conceived and designed the experiments. J.Z., Z.D., and X.Z. collected the samples. M.X., Y.W., W.X., and N.Z. performed the experiments. F.Z., Y.C., F.W., M.X., Y.W., and X.S. analyzed the data. Y.W. and M.X. wrote the article. All authors approved the final article.
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Xiang, M., Wang, Y., Xu, W. et al. Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10. J Assist Reprod Genet 38, 2791–2799 (2021). https://doi.org/10.1007/s10815-021-02295-x
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DOI: https://doi.org/10.1007/s10815-021-02295-x