Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility
Abstract
Teratozoospermia is a common factor associated with male infertility. However, teratozoospermia characterized by bubble-shaped acrosomes (BSAs) has not yet been identified in men and the causative genes are unknown. The present study is of a patient with severe teratozoospermia characterized by BSA and carrying a variant (c.1204G>A, p.Gly402Ser) of actin-like 7A (ACTL7A). For further verification, we generated an Actl7a-mutated mouse model (p.Gly407Ser) carrying an equivalent variant to that in the patient. We found that homozygous Actl7a-mutated (Actl7aMut/Mut) male mice were sterile, and all their sperm showed acrosomal abnormalities. We detected by transmission electron microscopy that during acrosomal biogenesis, the acrosome detaches from the nuclear membrane in Actl7aMut/Mut mice. Furthermore, mutant ACTL7A failed to attach to the acroplaxome and was discharged by cytoplasmic droplets, which led to the absence of ACTL7A in epididymal spermatozoa in mice. The mutant sperm failed to activate the oocyte, and sperm-borne oocyte activation factor phospholipase C zeta (PLCζ) discharge accompanied by ACTL7A was observed, leading to total fertilization failure (TFF). Immunoprecipitation followed by liquid chromatography-mass spectrometry showed that several differentially expressed proteins participate in acrosome assembly and actin filament organization. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF in the couple with an ACTL7A…
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Other genetic causes of sperm morphological abnormalities include mutations of SUN5, SPATA20, ACTL7A, and CCIN, which result in pinhead spermatozoa, acephalic spermatozoa syndrome, bubble-shaped acrosome, and severe head malformations, respectively.
“Other genetic causes of sperm morphological abnormalities include mutations of the SUN5, SPATA20, ACTL7A, and CCIN genes which result in pinhead spermatozoa and acephalic spermatozoa syndrome, bubble-shaped acrosome and severe head malformations, respectively (37,48,49,50).”
From Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review (2024) · cites this paper as [49]
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Prevalence of infertility and help seeking among 15 000 women and men
Datta, J., Palmer, M. J., Tanton, C., Gibson, L. J., Jones, K. G., Macdowall, W., Glasier, A., Sonnenberg, P., Field, N., Mercer, C. H., et al. (2016) · Human Reproduction · doi:10.1093/humrep/dew123 · Cited by 471 · see citing works
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Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review
Atmoko, W., Savira, M., Shah, R., Chung, E., & Agarwal, A. (2024) · Translational Andrology and Urology · doi:10.21037/tau-23-397 · Cited by 23 · see citing works
“Other genetic causes of sperm morphological abnormalities include mutations of the SUN5, SPATA20, ACTL7A, and CCIN genes which result in pinhead spermatozoa and acephalic spermatozoa syndrome, bubble-shaped acrosome and severe head malformations, respectively (37,48,49,50).”
- Authors
- Dai, J., Chen, Y., Li, Q., Zhang, T., Zhou, Q., Gong, F., Lu, G., Zheng, W., & Lin, G.
- Affiliations
- Central South University (CN)
- Xiangya Hospital Central South University (CN)
- National Health and Family Planning Commission (CN)
- Corresponding author
- Zheng, Wei
- Lin, Ge
- Venue
- Molecular Human Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-07-21
- Volume
- 28
- Issue
- 8
- ISSN
- 1360-9947 (ISSN-L)
- 1460-2407
- OpenAlex
- W4286382837
- Cited by
- 29
- References
- 1
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 8 · 2023: 7 · 2022: 1
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Molecular Human Reproduction (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81974230, 32000564)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
- Keywords
- teratozoospermia, male infertility, acrosome biogenesis, PLC, fertilization failure, actin filament organization, assisted oocyte activation, calcium ionophore
- MeSH terms
- Teratozoospermia, Acrosome, Animals, Humans, Infertility, Male, Male, Semen, Spermatozoa, Mice
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