SEPT12 mutations cause male infertility with defective sperm annulus
Open accessAbstract
Septins are members of the GTPase superfamily, which has been implicated in diverse cellular functions including cytokinesis and morphogenesis. Septin 12 (SEPT12) is a testis-specific gene critical for the terminal differentiation of male germ cells. We report the identification of two missense SEPT12 mutations, c.266C>T/p.Thr89Met and c.589G>A/p.Asp197Asn, in infertile men. Both mutations are located inside the GTPase domain and may alter the protein structure as suggested by in silico modeling. The p.Thr89Met mutation significantly reduced guanosine-5'-triphosphate (GTP) hydrolytic activity, and the p.Asp197Asn mutation (SEPT12(D197N)) interfered with GTP binding. Both mutant SEPT12 proteins restricted the filament formation of the wild-type SEPT12 in a dose-dependent manner. The patient carrying SEPT12(D197N) presented with oligoasthenozoospermia, whereas the SEPT12(T89M) patient had asthenoteratozoospermia. The characteristic sperm pathology of the SEPT12(D197N) patient included defective annulus with bent tail and loss of SEPT12 from the annulus of abnormal sperm. Our finding suggests loss-of-function mutations in SEPT12 disrupted sperm structural integrity by perturbing septin filament formation.
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Mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies.
“Several observational studies reported that mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies (51-53).”
From Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review (2024) · cites this paper as [53]
Sperm tail defects were found to correlate with several genetic defects.
“Aside from the defect mentioned above, sperm tail defects were also found to correlate with several genetic defects.”
From Isolated teratozoospermia: revisiting its relevance in male infertility: a narrative review (2024) · cites this paper as [53]
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Cites
Self- and actin-templated assembly of Mammalian septins
Kinoshita, M., Field, C. M., Coughlin, M. L., Straight, A. F., & Mitchison, T. J. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00366-0 · Cited by 526 · see citing works
Mechanism of Regulation of Prokaryotic Tubulin-like GTPase FtsZ by Membrane Protein EzrA
Chung, K.-M., Hsu, H.-H., Yeh, H.-Y., & Chang, B.-Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m605177200 · Cited by 32 · see citing works
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Research works printed but not linked: 2
- World Health Organization, WHO. 1999. World Health Organization. WHO Labora- tory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge: Cambridge University Press.
- Xie Y, Vessey JP, Konecna A, Dahm R, Macchi P, Kiebler MA. 2007. The GTP-binding protein Septin 7 is critical for dendrite branching and dendritic-spine morphology. Curr Biol 17:1746-1751. HUMAN MUTATION, Vol. 33, No. 4, 710-719, 2012
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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
“Several observational studies reported that mutations on DNAH1, SPEF2, and SEPT12 were correlated with sperm tail anomalies (51-53).”
- Authors
- Kuo, Y.-C., Lin, Y.-H., Chen, H.-I., Wang, Y.-Y., Chiou, Y.-W., Lin, H.-H., Pan, H.-A., Wu, C.-M., Su, S.-M., Hsu, C.-C., & Kuo, P.-L.
- Affiliations
- National Cheng Kung University (TW)
- Fu Jen Catholic University (TW)
- Kuo General Hospital (TW)
- China Medical University (TW)
- Corresponding author
- Kuo, Pao-Lin
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2012-02-20
- Volume
- 33
- Issue
- 4
- Pages
- 710-719
- ISSN
- 1059-7794 (ISSN-L)
- OpenAlex
- W2088190945
- Cited by
- 128
- References
- 2
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 13 · 2023: 8 · 2022: 14 · 2021: 9 · 2020: 10 · 2019: 14 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 14 · 2014: 10 · 2013: 2 · 2012: 1
- FWCI
- 9.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- Academia Sinica
- National Cheng Kung University Hospital
- National Cheng Kung University
- Institute of Biomedical Sciences, Academia Sinica
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- male infertility, missense mutations, GTPase domain, GTP hydrolysis, GTP binding, oligoasthenozoospermia, asthenoteratozoospermia, loss-of-function mutations, male germ cell differentiation
- MeSH terms
- Guanosine Triphosphate, Humans, Infertility, Male, Male, Sperm Motility, Spermatogenesis, Spermatozoa, Case-Control Studies, Mutation, Missense, Asthenozoospermia, Septins
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