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dc.contributor.authorYarham, John W.en_US
dc.contributor.authorLamichhane, Tek N.en_US
dc.contributor.authorPyle, Angelaen_US
dc.contributor.authorMattijssen, Sandyen_US
dc.contributor.authorBaruffini, Enricoen_US
dc.contributor.authorBruni, Francescoen_US
dc.contributor.authorDonnini, Claudiaen_US
dc.contributor.authorVassilev, Alexen_US
dc.contributor.authorHe, Langpingen_US
dc.contributor.authorBlakely, Emma L.en_US
dc.contributor.authorGriffin, Helenen_US
dc.contributor.authorSantibanez-Koref, Mauroen_US
dc.contributor.authorBindoff, Laurenceen_US
dc.contributor.authorFerrero, Ilianaen_US
dc.contributor.authorChinnery, Patrick F.en_US
dc.contributor.authorMcFarland, Roberten_US
dc.contributor.authorMaraia, Richard J.en_US
dc.contributor.authorTaylor, Robert W.en_US
dc.date.accessioned2015-03-30T08:56:57Z
dc.date.available2015-03-30T08:56:57Z
dc.date.issued2014-06-05eng
dc.identifier.issn1553-7390
dc.identifier.urihttps://hdl.handle.net/1956/9696
dc.description.abstractIdentifying the genetic basis for mitochondrial diseases is technically challenging given the size of the mitochondrial proteome and the heterogeneity of disease presentations. Using next-generation exome sequencing, we identified in a patient with severe combined mitochondrial respiratory chain defects and corresponding perturbation in mitochondrial protein synthesis, a homozygous p.Arg323Gln mutation in TRIT1. This gene encodes human tRNA isopentenyltransferase, which is responsible for i⁶A37 modification of the anticodon loops of a small subset of cytosolic and mitochondrial tRNAs. Deficiency of i⁶A37 was previously shown in yeast to decrease translational efficiency and fidelity in a codon-specific manner. Modelling of the p.Arg323Gln mutation on the co-crystal structure of the homologous yeast isopentenyltransferase bound to a substrate tRNA, indicates that it is one of a series of adjacent basic side chains that interact with the tRNA backbone of the anticodon stem, somewhat removed from the catalytic center. We show that patient cells bearing the p.Arg323Gln TRIT1 mutation are severely deficient in i⁶A37 in both cytosolic and mitochondrial tRNAs. Complete complementation of the i⁶A37 deficiency of both cytosolic and mitochondrial tRNAs was achieved by transduction of patient fibroblasts with wild-type TRIT1. Moreover, we show that a previously-reported pathogenic m.7480A>G mt-tRNASer(UCN) mutation in the anticodon loop sequence A36A37A38 recognised by TRIT1 causes a loss of i⁶A37 modification. These data demonstrate that deficiencies of i⁶A37 tRNA modification should be considered a potential mechanism of human disease caused by both nuclear gene and mitochondrial DNA mutations while providing insight into the structure and function of TRIT1 in the modification of cytosolic and mitochondrial tRNAs.en_US
dc.language.isoengeng
dc.publisherPLoSeng
dc.rightsPublic Domaineng
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/eng
dc.titleDefective i⁶A37 Modification of Mitochondrial and Cytosolic tRNAs Results from Pathogenic Mutations in TRIT1 and Its Substrate tRNAen_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2015-03-03T16:12:22Zen_US
dc.description.versionpublishedVersionen_US
dc.source.articlenumbere1004424
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1004424
dc.identifier.cristin1152409
dc.source.journalPLoS Genetics
dc.source.4010
dc.source.146
dc.subject.nsiVDP::Medical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714eng
dc.subject.nsiVDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714nob


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