2. Academic Validation
  3. Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice

Bi-allelic mutations of DNAH10 cause primary male infertility with asthenoteratozoospermia in humans and mice

  • Am J Hum Genet. 2021 Aug 5;108(8):1466-1477. doi: 10.1016/j.ajhg.2021.06.010.
Chaofeng Tu 1,  Jiangshan Cong 2,  Qianjun Zhang 1,  Xiaojin He 3,  Rui Zheng 4,  Xiaoxuan Yang 5,  Yang Gao 3,  Huan Wu 3,  Mingrong Lv 3,  Yayun Gu 6,  Shuai Lu 6,  Chunyu Liu 2,  Shixiong Tian 2,  Lanlan Meng 7,  Weili Wang 5,  Chen Tan 5,  Hongchuan Nie 7,  Dongyan Li 5,  Huan Zhang 7,  Fei Gong 1,  Liang Hu 1,  Guangxiu Lu 7,  Wenming Xu 4,  Ge Lin 1,  Feng Zhang 2,  Yunxia Cao 8,  Yue-Qiu Tan 9
Affiliations

Affiliations

  • 1 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China.
  • 2 Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), 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.
  • 3 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.
  • 4 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.
  • 5 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China.
  • 6 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 7 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China.
  • 8 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. Electronic address: [email protected].
  • 9 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410000, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410000, China. Electronic address: [email protected].
PMID: 34237282 DOI: 10.1016/j.ajhg.2021.06.010
Abstract

Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified several MMAF-associated genes, highlighting the condition's genetic heterogeneity. To further define the genetic causes underlying MMAF, we performed whole-exome sequencing in a cohort of 643 Chinese MMAF-affected men. Bi-allelic DNAH10 variants were identified in five individuals with MMAF from four unrelated families. These variants were either rare or absent in public population genome databases and were predicted to be deleterious by multiple bioinformatics tools. Morphological and ultrastructural analyses of the spermatozoa obtained from men harboring bi-allelic DNAH10 variants revealed striking flagellar defects with the absence of inner dynein arms (IDAs). DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes. Immunostaining analysis indicated that DNAH10 localized to the entire sperm flagellum of control spermatozoa. In contrast, spermatozoa from the men harboring bi-allelic DNAH10 variants exhibited an absence or markedly reduced staining intensity of DNAH10 and other IDA components, including DNAH2 and DNAH6. Furthermore, the phenotypes were recapitulated in mouse models lacking Dnah10 or expressing a disease-associated variant, confirming the involvement of DNAH10 in human MMAF. Altogether, our findings in humans and mice demonstrate that DNAH10 is essential for sperm flagellar assembly and that deleterious bi-allelic DNAH10 variants can cause male infertility with MMAF. These findings will provide guidance for genetic counseling and insights into the diagnosis of MMAF-associated asthenoteratozoospermia.

Keywords

DNAH10; MMAF; knockout mice; male infertility; sperm flagella.

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