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

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.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: xiaonan fu

LAB HEAD: Wenming Xu

PROVIDER: PXD011730 | Pride | 2019-11-12

REPOSITORIES: Pride

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

Shen Ying Y Zhang Feng F Li Fuping F Jiang Xiaohui X Yang Yihong Y Li Xiaoliang X Li Weiyu W Wang Xiang X Cheng Juan J Liu Mohan M Zhang Xueguang X Yuan Guiping G Pei Xue X Cai Kailai K Hu Fengyun F Sun Jianfeng J Yan Lanzhen L Tang Li L Jiang Chuan C Tu Wenling W Xu Jinyan J Wu Haojuan H Kong Weiqi W Li Shuying S Wang Ke K Sheng Kai K Zhao Xudong X Yue Huanxun H Yang Xiaoyu X Xu Wenming W

Nature communications 20190125 1

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 technolog ...[more]

PMID: 30683861

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Project description:Infertility is a widespread problem, affecting around 15% of couples worldwide, and is defined as the inability to achieve pregnancy within one year despite unprotected intercourse 1. Infertility can be caused by either male or female reproductive issues. Various medical conditions including malignancies, infections, urogenital conditions, or genetic causes can contribute to male infertility. However, 30-40% of men in their reproductive age are affected by idiopathic infertility, according to the guidelines of European Association of Urology (EAU) 1. Towards a better understanding of male infertility, it is mandatory to achieve a comprehensive understanding of involved genes, their RNA transcripts, and regulatory factors, including miRNAs, which influence the expression level of proteins. Therefore, such proteins need to be identified to investigate their role in spermatogenesis and male infertility. Although there are numerous studies on RNAs, including miRNAs related to male infertility 2-9, there are few studies aiming to cover the whole proteome of human sperm 10. The sperm transcriptome comprises a total of 60,505 transcripts including 11,688 differentially expressed transcripts in infertile and fertile men, as reported by Joshi et al. (2022)11. The entire sperm proteome encompasses 6871 proteins, as summarized by Castillo et al. (2018)10. Nevertheless, there is still a lack of high-throughput studies aiming to identify dysregulated proteins in sperm from subfertile men. Only few studies focused on comparisons of the sperm proteome in men with asthenozoospermia and there is virtually no proteomic studies of oligoasthenozoospermic men 12. Some identified proteins in sperm have functions in maintaining sperm motility and enabling fertilization and are involved in structural composition and/or energy metabolism 12-14 and others are not yet functionally characterized. In this study, we employed Mass spectrometry (MS) technology that is still rarely used in the field of human reproductive research to investigate the proteomic landscape of human sperm and their differential expression patterns in men with subfertility.

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

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

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