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Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy–like disease

Lookup NU author(s): Dr Veronika Boczonadi, Dr Monika Olahova, Dr Boglarka Bansagi, Dr Andreas Roos, Dr Vankateswara Ramesh, Professor Hanns Lochmuller, Dr Tuomo Polvikoski, Dr Roger Whittaker, Dr Angela Pyle, Dr Helen Griffin, Professor Robert Taylor, Professor Patrick Chinnery, Professor Rita Horvath

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Abstract

© 2018, American College of Medical Genetics and Genomics. 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.


Publication metadata

Author(s): Boczonadi V, King MS, Smith AC, Olahova M, Bansagi B, Roos A, Eyassu F, Borchers C, Ramesh V, Lochmuller H, Polvikoski T, Whittaker RG, Pyle A, Griffin H, Taylor RW, Chinnery PF, Robinson AJ, Kunji ERS, Horvath R

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2018

Volume: 20

Issue: 10

Pages: 1224-1235

Online publication date: 08/03/2018

Acceptance date: 21/11/2017

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/gim.2017.251

DOI: 10.1038/gim.2017.251


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