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dc.contributor.authorFriederich, Marisa W
dc.contributor.authorTimal, Sharita
dc.contributor.authorPowell, Christopher A
dc.contributor.authorDallabona, Cristina
dc.contributor.authorKurolap, Alina
dc.contributor.authorPalacios-Zambrano, Sara
dc.contributor.authorBratkovic, Drago
dc.contributor.authorDerks, Terry GJ
dc.contributor.authorBick, David
dc.contributor.authorBouman, Katelijne
dc.contributor.authorChatfield, Kathryn C
dc.contributor.authorDamouny-Naoum, Nadine
dc.contributor.authorDishop, Megan K
dc.contributor.authorFalik-Zaccai, Tzipora C
dc.contributor.authorFares, Fuad
dc.contributor.authorFedida, Ayalla
dc.contributor.authorFerrero, Ileana
dc.contributor.authorGallagher, Renata C
dc.contributor.authorGaresse, Rafael
dc.contributor.authorGilberti, Micol
dc.contributor.authorGonzález, Cristina
dc.contributor.authorGowan, Katherine
dc.contributor.authorHabib, Clair
dc.contributor.authorHalligan, Rebecca K
dc.contributor.authorKalfon, Limor
dc.contributor.authorKnight, Kaz
dc.contributor.authorLefeber, Dirk
dc.contributor.authorMamblona, Laura
dc.contributor.authorMandel, Hanna
dc.contributor.authorMory, Adi
dc.contributor.authorOttoson, John
dc.contributor.authorPaperna, Tamar
dc.contributor.authorPruijn, Ger JM
dc.contributor.authorRebelo Guiomar, Pedro
dc.contributor.authorSaada, Ann
dc.contributor.authorSainz, Bruno
dc.contributor.authorSalvemini, Hayley
dc.contributor.authorSchoots, Mirthe H
dc.contributor.authorSmeitink, Jan A
dc.contributor.authorSzukszto, Maciej J
dc.contributor.authorTer Horst, Hendrik J
dc.contributor.authorvan den Brandt, Frans
dc.contributor.authorvan Spronsen, Francjan J
dc.contributor.authorVeltman, Joris A
dc.contributor.authorWartchow, Eric
dc.contributor.authorWintjes, Liesbeth T
dc.contributor.authorZohar, Yaniv
dc.contributor.authorFernández-Moreno, Miguel A
dc.contributor.authorBaris, Hagit N
dc.contributor.authorDonnini, Claudia
dc.contributor.authorMinczuk, Michal
dc.contributor.authorRodenburg, Richard J
dc.contributor.authorVan Hove, Johan LK
dc.date.accessioned2018-12-08T00:32:04Z
dc.date.available2018-12-08T00:32:04Z
dc.date.issued2018-10-03
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286571
dc.description.abstractMitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNAGln). mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNAGln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMyocardium
dc.subjectFibroblasts
dc.subjectHumans
dc.subjectLentivirus
dc.subjectSaccharomyces cerevisiae
dc.subjectCardiomyopathies
dc.subjectMitochondrial Diseases
dc.subjectNitrogenous Group Transferases
dc.subjectProtein Subunits
dc.subjectRNA, Transfer
dc.subjectPedigree
dc.subjectProtein Biosynthesis
dc.subjectAmino Acid Sequence
dc.subjectOxidative Phosphorylation
dc.subjectMutation
dc.subjectModels, Molecular
dc.subjectInfant
dc.subjectInfant, Newborn
dc.subjectFemale
dc.subjectMale
dc.titlePathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameNat Commun
prism.startingPage4065
prism.volume9
dc.identifier.doi10.17863/CAM.33881
dcterms.dateAccepted2018-08-23
rioxxterms.versionofrecord10.1038/s41467-018-06250-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10-03
dc.contributor.orcidKurolap, Alina [0000-0002-7005-3621]
dc.contributor.orcidSainz, Bruno [0000-0003-4829-7651]
dc.contributor.orcidSmeitink, Jan A [0000-0003-1392-8038]
dc.contributor.orcidSzukszto, Maciej J [0000-0002-0463-652X]
dc.contributor.orcidMinczuk, Michal [0000-0001-8242-1420]
dc.contributor.orcidRodenburg, Richard J [0000-0001-5227-3527]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_00015/4)
pubs.funder-project-idMedical Research Council (MC_U105697135)
cam.issuedOnline2018-10-03


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International