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.

中文翻译：

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QRICH2的功能丧失突变导致男性不育，并伴有精子鞭毛的多种形态异常

鞭毛异常会损害精子运动并导致男性不育，然而，在鞭毛多种形态异常（MMAF）中发现的基因只能在少数情况下解释MMAF的致病机制。在这里，我们确定和功能特征的两个不育男性与两个近亲家庭的MMAF QRICH2的纯合功能丧失突变。值得注意的是，通过CRISPR-Cas9技术构建的Qrich2基因敲除（KO）雄性小鼠表现出MMAF表型和不育性。为了阐明Qrich2在精子鞭毛形成中起作用的机制，我们对KO和野生型小鼠的睾丸进行了蛋白质组学分析。此外，体外实验表明，QRICH2通过稳定和增强与鞭毛发育有关的蛋白质的表达而参与了精子鞭毛的发育。我们的发现有力地表明，人类QRICH2的基因突变可导致男性不育，而MMAF则认为QRICH2对精子鞭毛的形成至关重要。