Objective: Rare variants of CCNK (cyclin K) give rise to a syndrome with intellectual disability. The purpose of this study was to describe the genotype-phenotype spectrum of CCNK-related syndrome and the underlying molecular mechanisms of pathogenesis.
Methods: We identified a number of de novo CCNK variants in unrelated patients. We generated patient-induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) as disease models. In addition, we constructed NPC-specific Ccnk knockout (KO) mice and performed molecular and morphological analyses.
Results: We identified 2 new patients harboring CCNK missense variants and followed-up 3 previous reported patients, which constitute the largest patient population analysis of the disease. We demonstrate that both the patient-derived NPC models and the Ccnk KO mouse displayed deficient NPC proliferation and enhanced apoptotic cell death. RNA sequencing analyses of these NPC models uncovered transcriptomic signatures unique to CCNK-related syndrome, revealing significant changes in genes, including WNT5A, critical for progenitor proliferation and cell death. Further, to confirm WNT5A's role, we conducted rescue experiments using NPC and mouse models. We found that a Wnt5a inhibitor significantly increased proliferation and reduced apoptosis in NPCs derived from patients with CCNK-related syndrome and NPCs in the developing cortex of Ccnk KO mice.
Interpretation: We discussed the genotype-phenotype relationship of CCNK-related syndrome. Importantly, we demonstrated that CCNK plays critical roles in NPC proliferation and NPC apoptosis in vivo and in vitro. Together, our study highlights that Wnt5a may serve as a promising therapeutic target for the disease intervention. ANN NEUROL 2023;94:1136-1154.
© 2023 American Neurological Association.