含IQ基序的蛋白质可以被钙调蛋白(CaM)识别,并且对于许多生物过程至关重要。然而,含IQ基序的蛋白在精子发生中的作用尚不清楚.在这项研究中,我们在一个男性不育的中国家庭中发现了一个包含IQ基序的新基因H(IQCH)的功能丧失突变,其特征是鞭毛轴突破裂和线粒体结构异常。为了验证IQCH的功能,通过CRISPR-Cas9技术产生Iqch敲除(KO)小鼠。不出所料,IqchKO雄性小鼠表现出生育能力受损,这与顶体活性不足以及轴突和线粒体的结构异常有关,反映患者的表型。机械上,IQCH可以与CaM结合并随后调节RNA结合蛋白(尤其是HNRPAB)的表达,这是精子发生不可或缺的。总的来说,这项研究揭示了IQCH的功能,扩大了含有智商基序的蛋白质在生殖过程中的作用,为男性不育的遗传咨询和基因诊断提供重要指导。
IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar
axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the
axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.