Loss of DRC1 function leads to multiple morphological abnormalities of the sperm flagella and male infertility in human and mouse

Abstract

Motile cilia and flagellar defects can result in primary ciliary dyskinesia (PCD), which is a multisystemic genetic disorder that affects roughly 1:10000 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 prepubertal 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. Together, 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.

Molecular basis of the morphogenesis of sperm head and tail in mice

“…For example, the expression of DRC2, LRRC48 (DRC3), and GAS8 (DRC4) is reduced in DRC1 mutant mice. 83 The expression of DRC1, DRC3, DRC5, and DRC11 is reduced in Chlamydomonas DRC2 mutant. 92 Similarly, DRC7 interacts with DRC3, GAS8 (DRC4), and TCTE1 (DRC5), and the expression of those proteins are decreased in Drc7 –KO spermatozoa.…”

“…In the past few years, there has been rapid progress in the functional analysis of N‐DRC genes. Deletion or mutation of Drc1 , 83 Lrrc48 ( Drc3 ), 84 Tcte1 ( Drc5 ), 85 Drc7, 86 and Iqcg ( Drc9 ) 87 has been shown to cause male infertility in mice. Additionally, mutation of DRC1 , 83 CCDC65 ( DRC2 ), 88 , 89 and GAS8 ( DRC4 ) 90 was found to be associated with PCD in humans.…”

Genome-Wide Association Studies, Runs of Homozygosity Analysis, and Copy Number Variation Detection to Identify Reproduction-Related Genes in Bama Xiang Pigs

“…Gene CIB4 knockout (KO) mice are sterile because haploid differentiation becomes impaired ( 33 ). Knocking out the DRC1 gene in mice completely disorders the axoneme structure of sperm flagella, impairing sperm motility ( 34 ). Research in bulls shows that HADHA proteins are significantly more abundant in the immotile sperm of low-fertility males than in the sperm from high-fertility males ( 35 ).…”

A Phenotype and Genotype Case Report of a Neonate With Congenital Bilateral Coronary Artery Fistulas and Multiple Collateral Arteries

“…DRC1 is a key component of the nexin-dynein regulatory complex (N-DRC) and plays an important role in ciliary movement ( 25 ). Previous studies have reported that mutations in DRC1 largely result in primary ciliary dyskinesia ( 26 , 27 ), morphological abnormalities of the sperm flagella, and male infertility ( 28 ). Notably, a study revealed the central role of cilium and cilia transduced-cell signaling in the pathogenesis of CHD by the recessive forward genetic screen in mice.…”