2. Academic Validation
  3. Bi-allelic Mutations in TTC21A Induce Asthenoteratospermia in Humans and Mice

Bi-allelic Mutations in TTC21A Induce Asthenoteratospermia in Humans and Mice

  • Am J Hum Genet. 2019 Apr 4;104(4):738-748. doi: 10.1016/j.ajhg.2019.02.020.
Wangjie Liu 1,  Xiaojin He 2,  Shenmin Yang 3,  Raoudha Zouari 4,  Jiaxiong Wang 3,  Huan Wu 2,  Zine-Eddine Kherraf 5,  Chunyu Liu 1,  Charles Coutton 6,  Rui Zhao 7,  Dongdong Tang 2,  Shuyan Tang 8,  Mingrong Lv 2,  Youyan Fang 2,  Weiyu Li 1,  Hong Li 3,  Jianyuan Zhao 7,  Xue Wang 9,  Shimin Zhao 8,  Jingjing Zhang 2,  Christophe Arnoult 10,  Li Jin 7,  Zhiguo Zhang 2,  Pierre F Ray 5,  Yunxia Cao 11,  Feng Zhang 12
Affiliations

Affiliations

  • 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 211116, 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; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, 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 Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003 Tunis, Tunisia.
  • 5 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Institut National de la Santé et de la Recherche Médicale U1209, Centre National de la Recherche Scientifique UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM GI-DPI, Grenoble 38000, France.
  • 6 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Institut National de la Santé et de la Recherche Médicale U1209, Centre National de la Recherche Scientifique UMR 5309, Université Grenoble Alpes, Grenoble 38000, France; Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, Grenoble 38000, France.
  • 7 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.
  • 8 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.
  • 9 Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
  • 10 Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Institut National de la Santé et de la Recherche Médicale U1209, Centre National de la Recherche Scientifique UMR 5309, Université Grenoble Alpes, Grenoble 38000, France.
  • 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; Anhui Provincial Engineering Technology Research Center for Biopreservation and Artificial Organs, Hefei 230022, China. Electronic address: [email protected].
  • 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 211116, China; Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: [email protected].
PMID: 30929735 DOI: 10.1016/j.ajhg.2019.02.020
Abstract

Male infertility is a major concern affecting human reproductive health. Asthenoteratospermia can cause male infertility through reduced motility and abnormal morphology of spermatozoa. Several genes, including DNAH1 and some CFAP family members, are involved in multiple morphological abnormalities of the sperm flagella (MMAF). However, these known genes only account for approximately 60% of human MMAF cases. Here, we conducted further genetic analyses by using whole-exome sequencing in a cohort of 65 Han Chinese men with MMAF. Intriguingly, bi-allelic mutations of TTC21A (tetratricopeptide repeat domain 21A) were identified in three (5%) unrelated, MMAF-affected men, including two with homozygous stop-gain mutations and one with compound heterozygous mutations of TTC21A. Notably, these men consistently presented with MMAF and additional abnormalities of sperm head-tail conjunction. Furthermore, a homozygous TTC21A splicing mutation was identified in two Tunisian cases from an independent MMAF cohort. TTC21A is preferentially expressed in the testis and encodes an intraflagellar transport (IFT)-associated protein that possesses several tetratricopeptide repeat domains that perform functions crucial for ciliary function. To further investigate the potential roles of TTC21A in spermatogenesis, we generated Ttc21a mutant mice by using CRISPR-Cas9 technology and revealed sperm structural defects of the flagella and the connecting piece. Our consistent observations across human populations and in the mouse model strongly support the notion that bi-allelic mutations in TTC21A can induce asthenoteratospermia with defects of the sperm flagella and head-tail conjunction.

Keywords

CRISPR; MMAF; TTC21A; exome; flagella; male infertility; sequencing; sperm.

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