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A DNAH17 missense variant causes flagella destabilization and asthenozoospermia.

Authors
  • Zhang, Beibei1
  • Ma, Hui1
  • Khan, Teka1
  • Ma, Ao1
  • Li, Tao1
  • Zhang, Huan1
  • Gao, Jianing1
  • Zhou, Jianteng1
  • Li, Yang1
  • Yu, Changping1
  • Bao, Jianqiang1
  • Ali, Asim1
  • Murtaza, Ghulam1
  • Yin, Hao1
  • Gao, Qian1
  • Jiang, Xiaohua1
  • Zhang, Feng2, 3, 4
  • Liu, Chunyu2
  • Khan, Ihsan1
  • Zubair, Muhammad1
  • And 13 more
  • 1 The First Affiliated Hospital of University of Science and Technology of China, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China-Shenyang Jinghua Hospital Joint Center for Human Reproduction and Genetics, Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei, China. , (China)
  • 2 Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China. , (China)
  • 3 Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China. , (China)
  • 4 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China. , (China)
  • 5 Analysis and test center, Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou, China. , (China)
  • 6 Department of Respiration, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. , (China)
Type
Published Article
Journal
Journal of Experimental Medicine
Publisher
The Rockefeller University Press
Publication Date
Feb 03, 2020
Volume
217
Issue
2
Identifiers
DOI: 10.1084/jem.20182365
PMID: 31658987
Source
Medline
Language
English
License
Unknown

Abstract

Asthenozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. We recruited three Pakistani infertile brothers, born to first-cousin parents, displaying idiopathic asthenozoospermia but no ciliary-related symptoms. Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family. DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization. However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4-7 missing at principal piece and end piece than in controls. Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients' sperm tails. Further examinations revealed that the doublets 4-7 were destabilized largely due to the storage of sperm in epididymis. Altogether, we first report that a homozygous DNAH17 missense variant specifically induces doublets 4-7 destabilization and consequently causes asthenozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility. © 2019 Zhang et al.

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