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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\u20137 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\u2019 sperm tails. Further examinations revealed that the doublets 4\u20137 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\u20137 destabilization and consequently causes asthenozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility.<\/jats:p>","DOI":"10.1084\/jem.20182365","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T18:59:12Z","timestamp":1572289152000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":146,"title":["A <i>DNAH17<\/i> missense variant causes flagella destabilization and asthenozoospermia"],"prefix":"10.1084","volume":"217","author":[{"given":"Beibei","family":"Zhang","sequence":"first","affiliation":[{"name":"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 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