Abstract
Male infertility, a global public health problem, exhibits complex pathogenic causes and genetic factors deserve further discovery and study. We identified a novel homozygous missense mutation c.224A > C (p.D75A) in ACTL7A gene in two infertile brothers with teratozoospermia by whole-exome sequencing (WES). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) showed fertilization failure of the two affected couples. The three-dimensional (3D) models showed that a small section of α‐helix transformed into random coil in the mutant ACTL7A protein and mutant amino acid lacked a hydrogen bond with Ser170 amino acid. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. Furthermore, ACTL7A mutation caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients, which may be the key reasons for the fertilization failure after ICSI. Our findings expand the spectrum of ACTL7A mutations and provide novel theoretical basis for genetic counseling.
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All data and material included in this study are available from the corresponding author.
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The software used in this study is openly available and no code was utilized.
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Acknowledgements
We thank the family members for their participation in this study and the Research Core Facilities of College of Life Science (HUST) for providing instruments. Thanks to the support of the National Natural Science Foundation of China grants (81000079, 81170165 and 81870959 to X.Z.), Program for HUST Academic Frontier Youth Team (2016QYTD02) and Fundamental Research Funds for the Central Universities (HUST: 2019JYCXJJ035).
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Zhou, X., Xi, Q., Jia, W. et al. A novel homozygous mutation in ACTL7A leads to male infertility. Mol Genet Genomics 298, 353–360 (2023). https://doi.org/10.1007/s00438-022-01985-0
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DOI: https://doi.org/10.1007/s00438-022-01985-0