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Publications

Journal Article Ahead of print

PubMed: 41308990 DOI: 10.1016/j.jbc.2025.110983

Neurodevelopmental Disease-causing Variants in Choline Kinase CHKA Gene Couple Phosphatidylcholine Synthesis to Oxidative Stress Damage and Disease Etiology.

J Biol Chem

Authors: Mahtab Tavasoli, Mariam Alkandari, Gabriel Dorighello, Michael McPhee, Neale D Ridgway, Kathy Isaac, Stanislav Sokolenko, Reza Maroofian, Anju Shukla, Maha S Zaki, Henry Houlden, Christopher R McMaster

Affiliations

  • Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
  • AGADA Biosciences, Inc. Halifax, NS, Canada.
  • Department of Biochemistry and Molecular Biology, Dalhousie University.
  • Department of Process Engineering & Applied Science, Dalhousie University, Halifax, NS, Cana.
  • Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  • Department of Clinical Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
  • Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, WC1N 3BG, UK.
  • Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.

Abstract

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. Treatment with FCCP, a mitochondrial uncoupler, reduced ROS levels and attenuated lipid peroxidation in CHKA patient fibroblasts, suggesting a potential approach to therapeutic intervention.

MeSH

Choline, Choline Kinase, Genes, Stress, Physiological, Mitochondria, Oxidative Stress, Phosphatidylcholines, Fibroblasts, Therapeutics, Phospholipids, Neurodevelopment