CKAP5 deficiency induces premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is characterized by ovarian dysfunction that develops from diminished ovarian reserve (DOR). The exact aetiology of POI remains poorly understood. This study aims to elucidate the role of CKAP5 in the regulation of ovarian function and fertility. METHODS: Bulk RNA sequencing of granulosa cells was conducted in the control group and in the patients with DOR to screen for candidate genes, which were further validated by gene burden analysis in a next-generation sequencing cohort of POI and control individuals. Additionally, ovarian reserve was evaluated in heterozygous Ckap5 knockout mice, alongside the ovarian and oocyte single-cell transcriptome analysis. The regulatory mechanism of CKAP5 was studied through in vivo and in vitro experiments. FINDINGS: CKAP5 was identified as a key hub gene associated with ovarian ageing. Heterozygous Ckap5 knockout mice exhibited a POI-like phenotype, characterized by a reduced primordial follicle pool and accelerated follicular atresia. CKAP5 promotes autophagy via ATG7 and simultaneously supports DNA damage repair through the ATM. Finally, a variant in CKAP5 (NM_0001008938.4, c.630 + 7_630 + 11delCAAAA) was identified in patients with POI, resulting in protein truncation and loss of function. INTERPRETATION: CKAP5 deficiency induces premature ovarian insufficiency in both humans and mice. FUNDING: The National Key R&D Program of China (2017YFC1001100), the National Natural Science Foundation of China (81501248, 81471453 and 81801295), the Health Research Project of Hunan Provincial Health Commission (W20243018), the Science and Technology Innovation Program of Hunan Province (2021RC3031), the National Natural Science Foundation of Hunan Province (2022JJ30066), the Scientific Research Program of Hunan Provincial Health Commission (202205033471 and 21B0058), the Open Research Fund of Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control (HPKL2023013).