biostudies-literatureTavasoli MCanadian Institutes of Health Research110983https://www.ebi.ac.uk/biostudies/studies/S-EPMC12800699biostudies-literatureUnknown302(1)Biallelic variants in CHKA, which encodes the first enzyme in the CDP-choline pathway for the synthesis of phosphatidylcholine, cause an inherited disorder characterized by epilepsy, microcephaly, and intellectual disability. How a deficiency in CHKA activity manifests these neurological symptoms is poorly understood. In this study, we investigated patient-derived fibroblasts with CHKA missense variants to elucidate the molecular and biochemical mechanisms underlying the associated pathologies. CHKA variant fibroblasts exhibited impaired phospholipid and triacylglycerol synthesis, altered mitochondrial morphology and function, elevated reactive oxygen species (ROS) levels, and increased lipid peroxidation, suggesting a mechanism by which defective CHKA activity leads to lipid damage. TreatThe Journal of biological chemistryNeurodevelopmental disease-causing variants in choline kinase CHKA gene couple phosphatidylcholine synthesis to oxidative stress damage and disease etiology.PMC12800699SOP-159230Maroofian RHoulden HTavasoli MShukla AAlkandari MSokolenko SDorighello GMcPhee MZaki MSIsaac KMcMaster CRRidgway NDfalseNeurodevelopmental disease-causing variants in choline kinase CHKA gene couple phosphatidylcholine synthesis to oxidative stress damage and disease etiology.Biallelic variants in CHKA, which encodes the first enzyme in the CDP-choline pathway for the synthesis of phosphatidylcholine, cause an inherited disorder characterized by epilepsy, microcephaly, and intellectual disability. How a deficiency in CHKA activity manifests these neurological symptoms is poorly understood. In this study, we investigated patient-derived fibroblasts with CHKA missense variants to elucidate the molecular and biochemical mechanisms underlying the associated pathologies. CHKA variant fibroblasts exhibited impaired phospholipid and triacylglycerol synthesis, altered mitochondrial morphology and function, elevated reactive oxygen species (ROS) levels, and increased lipid peroxidation, suggesting a mechanism by which defective CHKA activity leads to lipid damage. Treat2025-01-01T00:00:00Z2025 Nov2026-06-06T14:55:22.534Z2026-06-01T03:07:50.238ZS-EPMC128006994130899010.1016/j.jbc.2025.110983