|Title||Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Boczonadi, V, King, MS, Smith, AC, Oláhová, M, Bansagi, B, Roos, A, Eyassu, F, Borchers, C, Ramesh, V, Lochmüller, H, Polvikoski, T, Whittaker, RG, Pyle, A, Griffin, H, Taylor, RW, Chinnery, PF, Robinson, AJ, Kunji, ERS, Horvath, R|
|Date Published||2018 10|
|Keywords||Adipates, Apoptosis, Cell Line, Dicarboxylic Acid Transporters, DNA, Mitochondrial, Fibroblasts, Homozygote, Humans, Mitochondria, Motor Neurons, Muscular Atrophy, Spinal, Mutation, Pipecolic Acids, Quinolinic Acid|
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.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC6004311|
|Grant List||MC_U105674181 / / Medical Research Council / United Kingdom |
G1000848 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council / United Kingdom
201064/Z/16/Z / / Wellcome Trust / United Kingdom
309548 / / European Research Council / International
MR/N025431/1 / / Medical Research Council / United Kingdom
G0800674 / / Medical Research Council / United Kingdom
203105/Z/16/Z / / Wellcome Trust / United Kingdom
MC_U105663139 / / Medical Research Council / United Kingdom
109915/Z/15/Z / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
109915 / / Wellcome Trust / United Kingdom