Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice,Clinical Genetics

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Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-10-17 , DOI: 10.1111/cge.13866
Beibei Zhang ₁ , Ihsan Khan ₁ , Chunyu Liu ₂ , Ao Ma ₁ , Asad Khan ₁ , Yuanwei Zhang ₁ , Huan Zhang ₁ , Mian Basit Shah Kakakhel ₁ , Jianteng Zhou ₁ , Wen Zhang ₃ , Yang Li ₁ , Asim Ali ₁ , Xiaohua Jiang ₁ , Ghulam Murtaza ₁ , Ranjha Khan ₁ , Muhammad Zubair ₁ , Limin Yuan ₄ , Mazhar Khan ₁ , Li Wang ₅ , Feng Zhang ₂ , Xiong Wang ₆ , Hui Ma ₁ , Qinghua Shi ₁

Affiliation

The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center of Genetics and Development, University of Science and Technology of China, Hefei 230027, China.
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China.
Fudan University Pudong Medical Center, Institutes of Biomedical Sciences, The Department of Systems Biology for Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200011, China.
Analysis and test center, Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou 225009, China.
The Center of Cryo-Electron Microscopy (CCEM), Zhejiang University, Hangzhou 310058, China.
Department of Reproductive Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, China.

Multiple morphological abnormalities of the flagella (MMAF) is a genetically heterogeneous disorder leading to male infertility. Recent studies have revealed that DNAH17 variants are associated with MMAF, yet there is no functional evidence in support of their pathnogenicity. Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF. Whole‐exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients. Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4–7 in sperm flagella of patients. Similar to those found in patients, Dnah17^−/− mice also displayed MMAF phenotype along with completely disorganized axonemal structures. Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly. Besides, we also noticed many elongating spermatids with a deformed nuclear shape and abnormal step 16 spermatids that failed to spermiate, which subsequently underwent apoptosis in Dnah17‐null mice. These findings present direct evidence establishing that DNAH17 is a MMAF‐related gene in humans and mice, extend the clinical interpretations of DNAH17 variants, and highlight an essential and complex role of DNAH17 in spermatogenesis.

更新日期：2020-10-17

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