2. Academic Validation
  3. Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility

Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility

  • Am J Hum Genet. 2021 Feb 4;108(2):309-323. doi: 10.1016/j.ajhg.2021.01.002.
Chunyu Liu 1,  Chaofeng Tu 2,  Lingbo Wang 3,  Huan Wu 4,  Brendan J Houston 5,  Francesco K Mastrorosa 6,  Wen Zhang 7,  Ying Shen 8,  Jiaxiong Wang 9,  Shixiong Tian 1,  Lanlan Meng 10,  Jiangshan Cong 1,  Shenmin Yang 9,  Yiwen Jiang 11,  Shuyan Tang 1,  Yuyan Zeng 11,  Mingrong Lv 4,  Ge Lin 2,  Jinsong Li 12,  Hexige Saiyin 11,  Xiaojin He 4,  Li Jin 11,  Aminata Touré 13,  Pierre F Ray 14,  Joris A Veltman 6,  Qinghua Shi 15,  Moira K O'Bryan 5,  Yunxia Cao 4,  Yue-Qiu Tan 16,  Feng Zhang 17
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.
  • 2 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, China.
  • 3 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 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.
  • 4 Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China.
  • 5 School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia; School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 6 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
  • 7 Fudan University Pudong Medical Center, Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 8 Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 9 State Key Laboratory of Reproductive Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China; Suzhou Municipal Hospital, Suzhou 215002, China.
  • 10 Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China.
  • 11 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.
  • 12 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.
  • 13 Team Genetics Epigenetics and Therapies of Infertility, Institute for Advance Biosciences, Grenoble Alpes University, INSERM U1209, Centre National de la Recherche Scientifique UMR 5309, Grenoble 38000, France.
  • 14 Team Genetics Epigenetics and Therapies of Infertility, Institute for Advance Biosciences, Grenoble Alpes University, INSERM U1209, Centre National de la Recherche Scientifique UMR 5309, Grenoble 38000, France; UM de genetique de l'infertilite et de diagnostic pre-implantatoire, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble 38000, France.
  • 15 The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
  • 16 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410000, China. Electronic address: [email protected].
  • 17 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. Electronic address: [email protected].
PMID: 33472045 DOI: 10.1016/j.ajhg.2021.01.002
Abstract

Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.

Keywords

CFAP47; CFAP65; ICSI; MMAF; cilia; flagellum; male infertility; mice; sperm.

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