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.
Highlights
According to the World Health Organization (WHO), men whose ejaculates have
Our study identifies a homozygous missense variant (c.G5408A) in DNAH17, a functionally uncharacterized gene, from a consanguineous Pakistani family with three offspring suffering from asthenozoospermia and provides genetic evidence that DNAH17 c.G5408A is pathogenic for asthenozoospermia using Dnah17M/M mice modeling the patients’ mutation
We demonstrate for the first time that DNAH17 is essential for sperm motility, and is the only known DNAH protein implicated in stabilizing flagellar structure, microtubule doublets (MTDs) 4–7
Summary
According to the World Health Organization (WHO), men whose ejaculates have
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