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The nexin-dynein regulatory complex (N-DRC) links neighboring doublet microtubules within flagella, serving as a central regulatory hub for motility in Chlamydomonas. Herein, we identified two homozygous DRC1 variants in human patients that were associated with multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility. Drc1\u2212\/\u2212, Drc1R554X\/R554X and Drc1W244X\/W244X mice on the C57BL\/6 background suffered from pre-pubertal mortality. However, when the ICR background was introduced, some of these mice were able to survive and recapitulate the MMAF phenotypes detected in human patients. By analyzing these animals, we determined that DRC1 is an essential regulator of N-DRC assembly in cilia and flagella. When DRC1 is absent, this results in the shortening of cilia and consequent impairment of their motility. Damage associated with DRC1 deficiency in sperm flagella was more pronounced than in cilia, as manifested by complete axoneme structural disorder in addition to the loss of the DRC structure. Altogether, these findings suggest that DRC1 is required for the structural stability of flagella but not cilia, emphasizing the key role of this protein in mammalian species.<\/jats:p>","DOI":"10.1093\/hmg\/ddab171","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T07:08:56Z","timestamp":1624345736000},"page":"1996-2011","source":"Crossref","is-referenced-by-count":61,"title":["Loss of DRC1 function leads to multiple morphological abnormalities of the sperm flagella and male infertility in human and mouse"],"prefix":"10.1093","volume":"30","author":[{"given":"Jintao","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojin","family":"He","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China"},{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-3839","authenticated-orcid":false,"given":"Huan","family":"Wu","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China"},{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiru","family":"Cheng","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China"},{"name":"Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People\u2019s Republic of China, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China"},{"name":"NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4556-8276","authenticated-orcid":false,"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, 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