Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.
Taylor, Robert W
Genetics in medicine : official journal of the American College of Medical Genetics
Wolters Kluwer Health
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Boczonadi, V., King, M., Smith, A., Olahova, M., Bansagi, B., Roos, A., Eyassu, F., et al. (2018). Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.. Genetics in medicine : official journal of the American College of Medical Genetics, 20 (10), 1224-1235. https://doi.org/10.1038/gim.2017.251
PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. CONCLUSION: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.
Motor Neurons, Cell Line, Mitochondria, Fibroblasts, Humans, Muscular Atrophy, Spinal, Pipecolic Acids, Quinolinic Acid, Dicarboxylic Acid Transporters, Mitochondrial Membrane Transport Proteins, DNA, Mitochondrial, Apoptosis, Homozygote, Mutation, Adipates
WELLCOME TRUST (101876/Z/13/Z)
WELLCOME TRUST (101876/B/13/A)
EC FP7 CP (305121)
Wellcome Trust (109915_A_15_Z)
External DOI: https://doi.org/10.1038/gim.2017.251
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287522