Int J Biol Sci 2023; 19(2):393-411. doi:10.7150/ijbs.76051 This issue Cite

Research Paper

Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans

Mingrong Lv1,2,3*, Dongdong Tang1,2,3*, Hui Yu1,6*, Hao Geng1,2,3*, Yiling Zhou7,8*, Zhongmei Shao1,6, Kuokuo Li1,2,3, Yang Gao2,3,4,5, Senchao Guo1,2, Chuan Xu1,2,3, Qing Tan1,9, Chunyu Liu7,8, Rui Guo2,3,4,5, Huan Wu1,2,3, Zongliu Duan1,2,3, Jingjing Zhang1,2,3, Guanxiong Wang1,2,3, Rong Hua2,3,4,5, Feifei Fu1,9, Kai Wang1,2, Yuping Xu1,2,3, Ping Zhou1,2,3, Zhaolian Wei1,2,3, Feng Zhang7,8✉, Yunxia Cao1,2,3✉, Xiaojin He1,2,3✉

1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
2. NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China.
3. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
4. Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei 230032, China.
5. Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China.
6. Department of Obstetrics and Gynecology, Fuyang Hospital of Anhui Medical University, Fuyang 236112, China.
7. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
8. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
9. Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
*These authors contributed equally to this work.

Citation:
Lv M, Tang D, Yu H, Geng H, Zhou Y, Shao Z, Li K, Gao Y, Guo S, Xu C, Tan Q, Liu C, Guo R, Wu H, Duan Z, Zhang J, Wang G, Hua R, Fu F, Wang K, Xu Y, Zhou P, Wei Z, Zhang F, Cao Y, He X. Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans. Int J Biol Sci 2023; 19(2):393-411. doi:10.7150/ijbs.76051. https://www.ijbs.com/v19p0393.htm
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Abstract

Graphic abstract

Asthenoteratozoospermia is one of the major factors for male infertility, whereas the causes of large numbers of cases are still unknown. We identified compound heterozygous variants of FSIP2 in three unrelated individuals from a cohort of 105 patients with asthenoteratozoospermia by exome sequencing. Deleterious FSIP2 variations caused severe disassembly of the fibrous sheath and axonemal defects. Intriguingly, spermatozoa in our study manifested “super-length” mitochondrial sheaths, increased levels of the mitochondrial sheath outer membrane protein TOMM20 and decreased mitochondrial ATP consumption. Dislocation or deletion of the annulus and reduction or dislocation of the annulus protein SEPT4 were also observed. While the lengthened mitochondrial sheaths were not presented in men harboring SEPT4 variants. Furthermore, female partners of two of three men achieved successful pregnancies following intracytoplasmic sperm injection (ICSI). Overall, we presume that FSIP2 may not only serve as a structural protein of the fibrous sheath but also as an intra-flagellar transporter involving in the axonemal assembly, mitochondrial selection and the termination of mitochondrial sheath extension during spermatogenesis, and ICSI is an effective treatment for individuals with FSIP2-associated asthenoteratozoospermia.

Keywords: Infertility, asthenoteratozoospermia, mitochondrial sheath, FSIP2, ICSI


Citation styles

APA
Lv, M., Tang, D., Yu, H., Geng, H., Zhou, Y., Shao, Z., Li, K., Gao, Y., Guo, S., Xu, C., Tan, Q., Liu, C., Guo, R., Wu, H., Duan, Z., Zhang, J., Wang, G., Hua, R., Fu, F., Wang, K., Xu, Y., Zhou, P., Wei, Z., Zhang, F., Cao, Y., He, X. (2023). Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans. International Journal of Biological Sciences, 19(2), 393-411. https://doi.org/10.7150/ijbs.76051.

ACS
Lv, M.; Tang, D.; Yu, H.; Geng, H.; Zhou, Y.; Shao, Z.; Li, K.; Gao, Y.; Guo, S.; Xu, C.; Tan, Q.; Liu, C.; Guo, R.; Wu, H.; Duan, Z.; Zhang, J.; Wang, G.; Hua, R.; Fu, F.; Wang, K.; Xu, Y.; Zhou, P.; Wei, Z.; Zhang, F.; Cao, Y.; He, X. Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans. Int. J. Biol. Sci. 2023, 19 (2), 393-411. DOI: 10.7150/ijbs.76051.

NLM
Lv M, Tang D, Yu H, Geng H, Zhou Y, Shao Z, Li K, Gao Y, Guo S, Xu C, Tan Q, Liu C, Guo R, Wu H, Duan Z, Zhang J, Wang G, Hua R, Fu F, Wang K, Xu Y, Zhou P, Wei Z, Zhang F, Cao Y, He X. Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans. Int J Biol Sci 2023; 19(2):393-411. doi:10.7150/ijbs.76051. https://www.ijbs.com/v19p0393.htm

CSE
Lv M, Tang D, Yu H, Geng H, Zhou Y, Shao Z, Li K, Gao Y, Guo S, Xu C, Tan Q, Liu C, Guo R, Wu H, Duan Z, Zhang J, Wang G, Hua R, Fu F, Wang K, Xu Y, Zhou P, Wei Z, Zhang F, Cao Y, He X. 2023. Novel FSIP2 Variants Induce Super-Length Mitochondrial Sheath and Asthenoteratozoospermia in Humans. Int J Biol Sci. 19(2):393-411.

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