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dc.contributor.authorBoczonadi, Veronikaen
dc.contributor.authorKing, Martinen
dc.contributor.authorSmith, Anthony Colinen
dc.contributor.authorOlahova, Monikaen
dc.contributor.authorBansagi, Boglarkaen
dc.contributor.authorRoos, Andreasen
dc.contributor.authorEyassu, Filmonen
dc.contributor.authorBorchers, Christophen
dc.contributor.authorRamesh, Venkateswaranen
dc.contributor.authorLochmüller, Hannsen
dc.contributor.authorPolvikoski, Tuomoen
dc.contributor.authorWhittaker, Roger Gen
dc.contributor.authorPyle, Angelaen
dc.contributor.authorGriffin, Helenen
dc.contributor.authorTaylor, Robert Wen
dc.contributor.authorChinnery, Patrick Francisen
dc.contributor.authorRobinson, Alan Jonathanen
dc.contributor.authorKunji, Edmund Richarden
dc.contributor.authorHorvath, Ritaen
dc.date.accessioned2018-02-06T13:54:53Z
dc.date.available2018-02-06T13:54:53Z
dc.date.issued2018-10en
dc.identifier.issn1098-3600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271725
dc.description.abstractPURPOSE: 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.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherSpringer Nature
dc.relation.isreplacedby1810/287522
dc.relation.isreplacedbyhttps://www.repository.cam.ac.uk/handle/1810/287522
dc.titleMitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.en
dc.typeArticle
prism.endingPage1235
prism.issueIdentifier10en
prism.publicationDate2018en
prism.publicationNameGenetics in medicine : official journal of the American College of Medical Geneticsen
prism.startingPage1224
prism.volume20en
dc.identifier.doi10.17863/CAM.18718
dcterms.dateAccepted2017-11-21en
rioxxterms.versionofrecord10.1038/gim.2017.251en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-10en
dc.contributor.orcidKing, Martin [0000-0001-6030-5154]
dc.contributor.orcidSmith, Anthony Colin [0000-0003-0141-0434]
dc.contributor.orcidGriffin, Helen [0000-0002-5288-3322]
dc.contributor.orcidChinnery, Patrick Francis [0000-0002-7065-6617]
dc.contributor.orcidRobinson, Alan Jonathan [0000-0001-9943-0059]
dc.contributor.orcidKunji, Edmund Richard [0000-0002-0610-4500]
dc.contributor.orcidHorvath, Rita [0000-0002-9841-170X]
dc.identifier.eissn1530-0366
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMedical Research Council (MC_U105674181)
pubs.funder-project-idWellcome Trust (101876/Z/13/Z)
pubs.funder-project-idWellcome Trust (101876/B/13/A)
pubs.funder-project-idMedical Research Council (MC_U105663139)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/R50564X/1)
pubs.funder-project-idMedical Research Council (MC_UU_00015/1)
rioxxterms.freetoread.startdate2018-09-08


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