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dc.contributor.authorBartsakoulia, Marinaen
dc.contributor.authorPyle, Angelaen
dc.contributor.authorTroncoso-Chandía, Diegoen
dc.contributor.authorVial-Brizzi, Josefaen
dc.contributor.authorPaz-Fiblas, Marysol Ven
dc.contributor.authorDuff, Jenniferen
dc.contributor.authorGriffin, Helenen
dc.contributor.authorBoczonadi, Veronikaen
dc.contributor.authorLochmüller, Hannsen
dc.contributor.authorKleinle, Stephanieen
dc.contributor.authorChinnery, Patricken
dc.contributor.authorGrünert, Sarahen
dc.contributor.authorKirschner, Janbernden
dc.contributor.authorEisner, Verónicaen
dc.contributor.authorHorvath, Ritaen
dc.date.accessioned2018-03-20T14:49:28Z
dc.date.available2018-03-20T14:49:28Z
dc.date.issued2018-04en
dc.identifier.issn0964-6906
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/274127
dc.description.abstractMitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency. MtDNA copy number was elevated and no deletions of the mtDNA were detected in muscle DNA. Whole exome sequencing identified a homozygous nonsense mutation (p.Q92*) in the MIEF2 gene encoding the mitochondrial dynamics protein of 49 kDa (MID49). Immunoblotting revealed increased levels of proteins promoting mitochondrial fusion (MFN2, OPA1) and decreased levels of the fission protein DRP1. Fibroblasts of the patient showed elongated mitochondria, and significantly higher frequency of fusion events, mtDNA abundance and aberrant mitochondrial cristae ultrastructure, compared to controls. Thus, our data suggest that mutations in MIEF2 result in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy
dc.format.mediumPrinten
dc.languageengen
dc.publisherOUP
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectFibroblastsen
dc.subjectHumansen
dc.subjectMuscular Diseasesen
dc.subjectElectron Transport Complex Ien
dc.subjectElectron Transport Complex IVen
dc.subjectGTP Phosphohydrolasesen
dc.subjectMitochondrial Proteinsen
dc.subjectPeptide Elongation Factorsen
dc.subjectMutation, Missenseen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectPrimary Cell Cultureen
dc.subjectMitochondrial Dynamicsen
dc.titleA novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies.en
dc.typeArticle
prism.endingPage1195
prism.issueIdentifier7en
prism.publicationDate2018en
prism.publicationNameHuman molecular geneticsen
prism.startingPage1186
prism.volume27en
dc.identifier.doi10.17863/CAM.21210
dcterms.dateAccepted2018-01-16en
rioxxterms.versionofrecord10.1093/hmg/ddy033en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-04en
dc.contributor.orcidGriffin, Helen [0000-0002-5288-3322]
dc.contributor.orcidChinnery, Patrick [0000-0002-7065-6617]
dc.contributor.orcidGrünert, Sarah [0000-0001-5986-0468]
dc.contributor.orcidKirschner, Janbernd [0000-0003-1618-7386]
dc.contributor.orcidHorvath, Rita [0000-0002-9841-170X]
dc.identifier.eissn1460-2083
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (101876/Z/13/Z)
pubs.funder-project-idWELLCOME TRUST (101876/B/13/A)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idEC FP7 CP (305121)
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
pubs.funder-project-idMRC (MR/N025431/2)
cam.orpheus.successThu Jan 30 12:59:07 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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