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

Nat Commun. 2019 Jan 25;10(1):433. doi: 10.1038/s41467-018-08182-x.

Ying Shen ¹, Feng Zhang ² ³ ⁴, Fuping Li ⁵ ⁶, Xiaohui Jiang ⁵ ⁶, Yihong Yang ⁷, Xiaoliang Li ¹, Weiyu Li ², Xiang Wang ¹, Juan Cheng ⁸, Mohan Liu ⁹, Xueguang Zhang ¹, Guiping Yuan ¹⁰, Xue Pei ⁹, Kailai Cai ¹¹, Fengyun Hu ¹², Jianfeng Sun ¹³, Lanzhen Yan ¹⁴, Li Tang ¹, Chuan Jiang ¹, Wenling Tu ⁹, Jinyan Xu ⁵ ⁶, Haojuan Wu ⁸, Weiqi Kong ¹, Shuying Li ¹, Ke Wang ¹, Kai Sheng ¹, Xudong Zhao ¹⁵ ¹⁶, Huanxun Yue ¹⁷ ¹⁸, Xiaoyu Yang ¹⁹, Wenming Xu ²⁰

Affiliations

1 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, 610041, Chengdu, China.
2 Obstetrics and Gynecology Hospital, Institute of Metabolism and Integrative Biology, School of Life Sciences, Fudan University, 200011, Shanghai, China.
3 State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, 211116, Nanjing, China.
4 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011, Shanghai, China.
5 Human Sperm Bank, West China Second University Hospital, Sichuan University, 610041, Chengdu, China.
6 Key Laboratory of Birth Defects and Related Disease of Women and Children (Sichuan University), Ministry of Education, 610041, Chengdu, China.
7 Center of Reproductive Medicine, West China Second University Hospital, Sichuan University, 610041, Chengdu, China.
8 Southwest Medical University, 646000, Luzhou, China.
9 Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China.
10 Analytical & Testing Center, Sichuan University, 610041, Chengdu, China.
11 Chengdu Research Base of Giant Panda Breeding, 610041, Chengdu, China.
12 Auckland University, 1142, Auckland, New Zealand.
13 Teaching Hospital of Chengdu University of TCM, 610041, Chengdu, China.
14 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650000, Kunming, China.
15 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650000, Kunming, China. [email protected].
16 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, 650223, Kunming, China. [email protected].
17 Human Sperm Bank, West China Second University Hospital, Sichuan University, 610041, Chengdu, China. [email protected].
18 Key Laboratory of Birth Defects and Related Disease of Women and Children (Sichuan University), Ministry of Education, 610041, Chengdu, China. [email protected].
19 State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, The First Hospital, Nanjing Medical University, 210029, Nanjing, China. [email protected].
20 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, 610041, Chengdu, China. [email protected].

PMID: 30683861 DOI: 10.1038/s41467-018-08182-x

Abstract

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.

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