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http://purl.uniprot.org/citations/29517768http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/29517768http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/29517768http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.org/dc/terms/identifier"doi:10.1038/gim.2017.251"xsd:string
http://purl.uniprot.org/citations/29517768http://purl.org/dc/terms/identifier"doi:10.1038/gim.2017.251"xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Griffin H."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Griffin H."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Smith A.C."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Smith A.C."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Roos A."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Roos A."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Robinson A.J."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Robinson A.J."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Horvath R."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Horvath R."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Lochmueller H."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Lochmueller H."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Taylor R.W."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Taylor R.W."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"King M.S."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"King M.S."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Kunji E.R.S."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Kunji E.R.S."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Chinnery P.F."xsd:string
http://purl.uniprot.org/citations/29517768http://purl.uniprot.org/core/author"Chinnery P.F."xsd:string
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