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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, Professor Roger Whittaker, Dr Angela Pyle, Dr Helen GriffinORCiD, Professor Robert Taylor, Professor Patrick Chinnery, Professor Rita HorvathORCiD
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© 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.
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
Print publication date: 01/10/2018
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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