Biallelic <i>ATP8B3</i> variants cause male infertility and fertilization failure in humans

Daijuan Chen; Guicheng Zhao; Yunchuan Tian; Xiang Wang; Xinyao Tang; Shikun Zhao; Jun Ma; Xiaodong Wang; Yihong Yang; Ying Shen

doi:10.1016/j.jgg.2026.09.004

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2026 > Accepted Manuscript

PDF( 0 KB)

Biallelic ATP8B3 variants cause male infertility and fertilization failure in humans

doi: 10.1016/j.jgg.2026.09.004

a. Department of Genetic Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
b. Department of Obstetrics/Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
c. Reproductive Andrology and Sichuan Human Sperm Bank, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China;
d. Reproduction Medical Center, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, Sichuan University, Chengdu, Sichuan 610041, China;
e. NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, Sichuan 610041, China

Funds:

This work was supported by Sichuan Science and Technology Program (2025ZNSFSC1670), and the National Natural Science Foundation of China (82471650).

Received Date: 2026-05-22
Accepted Date: 2026-09-06
Rev Recd Date: 2026-09-03

Available Online: 2026-09-20

Abstract

FullText(HTML)

References(20)

References

Bryde S., Hennrich H., Verhulst PM., Devaux PF., Lenoir G., Holthuis JC., 2010. CDC50 proteins are critical components of the human class-1 P4-ATPase transport machinery. J. Biol. Chem. 285, 40562-40572.

Campos G., Sciorio R., Esteves SC., 2023. Total fertilization failure after ICSI: insights into pathophysiology, diagnosis, and management through artificial oocyte activation. Hum. Reprod. Update 29, 369-394.

Dai J., Zhang T., Guo J., Zhou Q., Gu Y., Zhang J., Hu L., Zong Y., Song J., Zhang S., et al., 2021. Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice. Am. J. Hum. Genet. 108, 469-481.

Gao T., Liu Y., Li J., Zhang Y., Wu B., 2025. Function of manchette and intra-manchette transport in spermatogenesis and male fertility. Cell. Commun. Signal. 23, 250-271.

Georgadaki K., Khoury N., Spandidos DA., Zoumpourlis V., 2016. The molecular basis of fertilization (review). Int. J. Mol. Med. 38, 979-986.

Gong EY., Park E., Lee HJ., Lee K., 2009. Expression of Atp8b3 in murine testis and its characterization as a testis specific P-type ATPase. Reproduction 137, 345-351.

Ito C., Akutsu H., Yao R., Kyono K., Suzuki-Toyota F., Toyama Y., Maekawa M., Noda T., Toshimori K., 2009. Oocyte activation ability correlates with head flatness and presence of perinuclear theca substance in human and mouse sperm. Hum. Reprod. 24, 2588-2595.

Lehti MS., Sironen A., 2016. Formation and function of the manchette and flagellum during spermatogenesis. Reproduction 151, R43-R54.

Nicholson CL., Dean M., Attia A., Milne PA., Martins da Silva S., 2024. Artificial oocyte activation improves ICSI outcomes following unexplained fertilization abnormalities. Reprod. Biomed. Online 49, 104327-104335.

Oko R., Sutovsky P., 2009. Biogenesis of sperm perinuclear theca and its role in sperm functional competence and fertilization. J. Reprod. Immunol. 83, 2-7.

Osada N., Hashimoto K., Hirai M., Kusuda J., 2007. Aberrant termination of reproduction-related TMEM30C transcripts in the hominoids. Gene 392, 151-156.

Shin HW., Takatsu H., 2025. Substrates, regulation, cellular functions, and disease associations of P4-ATPases. Commun. Biol. 8, 135-150.

Swain JE., Pool TB., 2008. ART failure: oocyte contributions to unsuccessful fertilization. Hum, Reprod, Update 14, 431-446.

Sebastian TT., Baldridge RD., Xu P., Graham TR., 2012. Phospholipid flippases: building asymmetric membranes and transport vesicles. Annu. Rev. Cell. Dev. Biol. 28, 345-370.

Wang J., Zhang J., Sun X., Lin Y., Cai L., Cui Y., Liu J., Liu M., Yang X., 2021. Novel bi-allelic variants in ACTL7A are associated with male infertility and total fertilization failure. Hum. Reprod. 36, 3161-3169.

Wang L., Beserra C., Garbers DL., 2004. A novel aminophospholipid transporter exclusively expressed in spermatozoa is required for membrane lipid asymmetry and normal fertilization. Dev. Biol. 267, 203-215.

Wassarman PM., 1999. Mammalian fertilization: molecular aspects of gamete adhesion, exocytosis, and fusion. Cell 96, 175-183.

Wei YL., Yang WX., 2018. The acroframosome-acroplaxome-manchette axis may function in sperm head shaping and male fertility. Gene 660, 28-40.

Xin A., Qu R., Chen G., Zhang L., Chen J., Tao C., Fu J., Tang J., Ru Y., Chen Y., et al., 2020. Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest. Sci. Adv. 6, eaaz4796-4804.

Yan Z., Fan Y., Wang F., Yan Z., Li M., Ouyang J., Wu L., Yin M., Zhao J., Kuang Y., et al., 2020. Novel mutations in PLCZ1 cause male infertility due to fertilization failure or poor fertilization. Hum. Reprod. 35, 472-481.

Relative Articles

Supplements(0)

Cited By

Proportional views