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Am J Hum Genet. 2019 Dec 5;105(6):1168-1181. doi: 10.1016/j.ajhg.2019.10.010. Epub 2019 Nov 14.

Bi-allelic Mutations in TTC29 Cause Male Subfertility with Asthenoteratospermia in Humans and Mice.

Author information

1
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
2
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230022, China.
3
State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China; Suzhou Municipal Hospital, Suzhou 215002, China.
4
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
5
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
6
Suzhou Municipal Hospital, Suzhou 215002, China.
7
State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
8
Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei 230022, China.
9
Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
10
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China.
11
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230022, China. Electronic address: caoyunxia6@126.com.
12
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhangfeng@fudan.edu.cn.

Abstract

As a type of severe asthenoteratospermia, multiple morphological abnormalities of the flagella (MMAF) are characterized by the presence of immotile spermatozoa with severe flagellar malformations. MMAF is a genetically heterogeneous disorder, and the known MMAF-associated genes can only account for approximately 60% of human MMAF cases. Here we conducted whole-exome sequencing and identified bi-allelic truncating mutations of the TTC29 (tetratricopeptide repeat domain 29) gene in three (3.8%) unrelated cases from a cohort of 80 MMAF-affected Han Chinese men. TTC29 is preferentially expressed in the testis, and TTC29 protein contains the tetratricopeptide repeat domains that play an important role in cilia- and flagella-associated functions. All of the men harboring TTC29 mutations presented a typical MMAF phenotype and dramatic disorganization in axonemal and/or other peri-axonemal structures. Immunofluorescence assays of spermatozoa from men harboring TTC29 mutations showed deficiency of TTC29 and remarkably reduced staining of intraflagellar-transport-complex-B-associated proteins (TTC30A and IFT52). We also generated a Ttc29-mutated mouse model through the use of CRISPR-Cas9 technology. Remarkably, Ttc29-mutated male mice also presented reduced sperm motility, abnormal flagellar ultrastructure, and male subfertility. Furthermore, intracytoplasmic sperm injections performed for Ttc29-mutated mice and men harboring TTC29 mutations consistently acquired satisfactory outcomes. Collectively, our experimental observations in humans and mice suggest that bi-allelic mutations in TTC29, as an important genetic pathogeny, can induce MMAF-related asthenoteratospermia. Our study also provided effective guidance for clinical diagnosis and assisted reproduction treatments.

KEYWORDS:

CRISPR; MMAF; TTC29; WES; asthenoteratospermia; intraflagellar transport; male subfertility; mouse model; sequencing; sperm flagella

PMID:
31735294
DOI:
10.1016/j.ajhg.2019.10.010

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