Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.
Whittaker, Roger G
Taylor, Robert W
Genetics in medicine : official journal of the American College of Medical Genetics
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Boczonadi, V., King, M., Smith, A. C., 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: Members of the mitochondrial carrier family (SLC25) transport metabolites, nucleotides, co-factors and inorganic ions across the mitochondrial inner membrane. Methods: We identified a pathogenic variant in a novel mitochondrial carrier gene in a patient by whole exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modelling 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.
Medical Research Council (MC_U105674181)
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (101876/B/13/A)
Medical Research Council (MC_U105663139)
Biotechnology and Biological Sciences Research Council (BB/R50564X/1)
Medical Research Council (MC_UU_00015/1)
External DOI: https://doi.org/10.1038/gim.2017.251
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271725