Loss-of-function mutations in QRICH2 cause male infertility with multiple morphological abnormalities of the sperm flagella

• Published in: Nature communications Vol. 10; no. 1; pp. 433 - 15
• Main Authors: Shen, Ying, Zhang, Feng, Li, Fuping, Jiang, Xiaohui, Yang, Yihong, Li, Xiaoliang, Li, Weiyu, Wang, Xiang, Cheng, Juan, Liu, Mohan, Zhang, Xueguang, Yuan, Guiping, Pei, Xue, Cai, Kailai, Hu, Fengyun, Sun, Jianfeng, Yan, Lanzhen, Tang, Li, Jiang, Chuan, Tu, Wenling, Xu, Jinyan, Wu, Haojuan, Kong, Weiqi, Li, Shuying, Wang, Ke, Sheng, Kai, Zhao, Xudong, Yue, Huanxun, Yang, Xiaoyu, Xu, Wenming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 13/51; 38/23; 631/208; 631/208/1516; 631/208/4041; 631/208/514/2254; 82/29; 82/80; A Kinase Anchor Proteins - deficiency; A Kinase Anchor Proteins - genetics; Adult; Animals; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; Consanguinity; Crystallography; Gating; Gating and risering; Gene Expression; Gene Expression Profiling; Heat-Shock Proteins - deficiency; Heat-Shock Proteins - genetics; Homeostasis; Humanities and Social Sciences; Humans; Infertility; Infertility, Male - genetics; Infertility, Male - metabolism; Infertility, Male - pathology; Loss of Function Mutation; Magnesium; Male; Mice; Mice, Knockout; Microtubule Proteins - genetics; multidisciplinary; Mutation; Pedigree; Phosphoproteins - deficiency; Phosphoproteins - genetics; Science; Science (multidisciplinary); Sperm Motility; Sperm Tail - metabolism; Sperm Tail - pathology; Sperm Tail - ultrastructure; Testis - chemistry; Testis - metabolism; Whole Genome Sequencing; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08182-x

Aberrant sperm flagella impair sperm motility and cause male infertility, yet the genes which have been identified in multiple morphological abnormalities of the flagella (MMAF) can only explain the pathogenic mechanisms of MMAF in a small number of cases. Here, we identify and functionally characterize homozygous loss-of-function mutations of QRICH2 in two infertile males with MMAF from two consanguineous families. Remarkably, Qrich2 knock-out (KO) male mice constructed by CRISPR-Cas9 technology present MMAF phenotypes and sterility. To elucidate the mechanisms of Qrich2 functioning in sperm flagellar formation, we perform proteomic analysis on the testes of KO and wild-type mice. Furthermore, in vitro experiments indicate that QRICH2 is involved in sperm flagellar development through stabilizing and enhancing the expression of proteins related to flagellar development. Our findings strongly suggest that the genetic mutations of human QRICH2 can lead to male infertility with MMAF and that QRICH2 is essential for sperm flagellar formation. Multiple morphological abnormalities of the sperm flagella (MMAF) is a cause of male infertility. Here the authors identify homozygous nonsense mutations of the glutamine rich 2 ( QRICH2 ) gene in two MMAF patients from 2 consanguineous families and show using QRICH2 knockout mice that the protein is required for sperm flagellar formation and motility.