Loss of DRC1 function leads to multiple morphological abnormalities of the sperm flagella and male infertility in human and mouse. Issue 21 (24th June 2021)

• Record Type: Journal Article
• Authors: Zhang, Jintao; He, Xiaojin; Wu, Huan; Zhang, Xin; Yang, Shenmin; Liu, Chunyu; Liu, Siyu; Hua, Rong; Zhou, Shushu; Zhao, Shuqin; Hu, Fan; Zhang, Junqiang; Liu, Wangjie; Cheng, Huiru; Gao, Yang; Zhang, Feng; Cao, Yunxia; Liu, Mingxi
• Is Part Of: Human molecular genetics. Volume 30:Issue 21(2021)
• Page Start: 1996
• Page End: 2011
• Publication Date: 2021-06-24
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddab171
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Motile cilia and flagellar defects can result in primary ciliary dyskinesia, which is a multisystemic genetic disorder that affects roughly 1:10 000 individuals. 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 −/−, Drc1 R554X/R554X and Drc1 W244X/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.