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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 Lv^1,2,3*, Dongdong Tang^1,2,3*, Hui Yu^1,6*, Hao Geng^1,2,3*, Yiling Zhou^7,8*, Zhongmei Shao^1,6, Kuokuo Li^1,2,3, Yang Gao^2,3,4,5, Senchao Guo^1,2, Chuan Xu^1,2,3, Qing Tan^1,9, Chunyu Liu^7,8, Rui Guo^2,3,4,5, Huan Wu^1,2,3, Zongliu Duan^1,2,3, Jingjing Zhang^1,2,3, Guanxiong Wang^1,2,3, Rong Hua^2,3,4,5, Feifei Fu^1,9, Kai Wang^1,2, Yuping Xu^1,2,3, Ping Zhou^1,2,3, Zhaolian Wei^1,2,3, Feng Zhang^7,8✉, Yunxia Cao^1,2,3✉, Xiaojin He^1,2,3✉

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.

✉ Corresponding authors: Xiaojin He, MD, PhD, Professor of Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, China. E-mail: hxj0117com; Yunxia Cao, MD, PhD, Professor of Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, China. E-mail: caoyunxia6com; Feng Zhang, PhD, Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China. E-mail: zhangfengedu.cn. More

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

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