A <i>DNAH17</i> missense variant causes flagella destabilization and asthenozoospermia

Beibei Zhang(University of Science and Technology of China), Hui Ma(University of Science and Technology of China), Teka Khan(University of Science and Technology of China), Ao Ma(University of Science and Technology of China), Tao Li(University of Science and Technology of China), Huan Zhang(University of Science and Technology of China), Jianing Gao(University of Science and Technology of China), Jianteng Zhou(University of Science and Technology of China), Yang Li(University of Science and Technology of China), Changping Yu(University of Science and Technology of China), Jianqiang Bao(University of Science and Technology of China), Asim Ali(University of Science and Technology of China), Ghulam Murtaza(University of Science and Technology of China), Hao Yin(University of Science and Technology of China), Qian Gao(University of Science and Technology of China), Xiaohua Jiang(University of Science and Technology of China), Feng Zhang(Fudan University), Chunyu Liu(Fudan University), Ihsan Khan(University of Science and Technology of China), Muhammad Zubair(University of Science and Technology of China), Hafiz Muhammad Jafar Hussain(University of Science and Technology of China), Ranjha Khan(University of Science and Technology of China), Ayesha Yousaf(University of Science and Technology of China), Limin Yuan(Yangzhou University), Yan Lu(Yangzhou University), Xiaoling Xu(University of Science and Technology of China), Yun Wang(University of Science and Technology of China), Qizhao Tao(University of Science and Technology of China), Qiaomei Hao(University of Science and Technology of China), Hui Fang(University of Science and Technology of China), Hongtao Cheng(University of Science and Technology of China), Yuanwei Zhang(University of Science and Technology of China), Qinghua Shi(University of Science and Technology of China)
The Journal of Experimental Medicine
October 28, 2019
10.1084/jem.20182365
Cited by 159Open Access
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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.

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