Key Laboratory of Obstetrics, Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
Elife. 2024 Jul 19;12:RP88905. doi: 10.7554/eLife.88905.
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 () in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the 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.
含 IQ 基序的蛋白质可以被钙调蛋白（CaM）识别，对许多生物过程是必不可少的。然而，含 IQ 基序的蛋白质在精子发生中的作用在很大程度上是未知的。在这项研究中，我们在中国一个具有特征性的裂头体轴丝和异常线粒体结构的男性不育的家族中，鉴定了一个新型基因 IQ 基序含 H（）的功能丧失突变。为了验证 IQCH 的功能，我们通过 CRISPR-Cas9 技术生成了 IQCH 敲除（KO）小鼠。正如预期的那样，IQCH KO 雄性小鼠表现出生育能力受损，这与顶体酶活性不足以及轴丝和线粒体的异常结构有关，反映了患者的表型。从机制上讲，IQCH 可以与 CaM 结合，随后调节 RNA 结合蛋白（特别是 HNRPAB）的表达，这对精子发生是必不可少的。总的来说，这项研究揭示了 IQCH 的功能，扩展了含 IQ 基序的蛋白质在生殖过程中的作用，并为男性不育的遗传咨询和遗传诊断提供了重要指导。
