CCDC174 deficiency impaired human fertility by affecting the alternative splicing of maternal mRNAs

Precise regulation of alternative splicing (AS) of maternal mRNAs is crucial for maintaining mRNA homeostasis and for acquiring oocyte competence. However, the regulatory factors and mechanisms of AS regulating oocyte competence and human fertility remain largely unknown. Here, we identified biallelic variants in CCDC174 that cause human oocyte competence defects and female infertility. Oocyte-specific knockout of Ccdc174 resulted in oocyte maturation arrest and female infertility in mice, and transcriptomic and proteomic analyses indicated that deletion of Ccdc174 disrupted mRNA and protein homeostasis as well as AS in oocytes. Importantly, we found that CCDC174 interacted with the splicing machinery-related PRP19/CDC5L complex, and loss of CCDC174 led to aberrant activation of the expression of these complex members in oocytes. In addition, in vitro studies indicated that patient-derived variants impaired the expression of CCDC174 and its binding to RNAs or CDC5L. Taken together, our study not only show that CCDC174 is a novel AS regulator that maintains mRNA homeostasis and oocyte competence, but also decipher the critical role of CCDC174 deficiency in the pathogenesis of female infertility.