Loss of DRC1 Function Leads to Multiple Morphological Abnormalities of the Sperm Flagella and Male Infertility in Human and Mouse

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2021 Jun 25

PMID 34169321

Citations 21

Authors

Jintao Zhang

Xiaojin He

Huan Wu

Xin Zhang

Shenmin Yang

Chunyu Liu

Siyu Liu

Rong Hua

Shushu Zhou

Shuqin Zhao

Fan Hu

Junqiang Zhang

Wangjie Liu

Huiru Cheng

Yang Gao

Feng Zhang

Yunxia Cao

Mingxi Liu

Affiliations

Soon will be listed here.

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-/-, 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.

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