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Clonal expansion of mtDNA deletions: different disease models assessed by digital droplet PCR in single muscle cells.

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cam.issuedOnline2018-08-03
dc.contributor.authorTrifunov, Selena
dc.contributor.authorPyle, Angela
dc.contributor.authorValentino, Maria Lucia
dc.contributor.authorLiguori, Rocco
dc.contributor.authorYu-Wai-Man, Patrick
dc.contributor.authorBurté, Florence
dc.contributor.authorDuff, Jennifer
dc.contributor.authorKleinle, Stephanie
dc.contributor.authorDiebold, Isabel
dc.contributor.authorRugolo, Michela
dc.contributor.authorHorvath, Rita
dc.contributor.authorCarelli, Valerio
dc.contributor.orcidKleinle, Stephanie [0000-0003-0135-7143]
dc.date.accessioned2018-10-03T04:45:57Z
dc.date.available2018-10-03T04:45:57Z
dc.date.issued2018-08-03
dc.description.abstractDeletions in mitochondrial DNA (mtDNA) are an important cause of human disease and their accumulation has been implicated in the ageing process. As mtDNA is a high copy number genome, the coexistence of deleted and wild-type mtDNA molecules within a single cell defines heteroplasmy. When deleted mtDNA molecules, driven by intracellular clonal expansion, reach a sufficiently high level, a biochemical defect emerges, contributing to the appearance and progression of clinical pathology. Consequently, it is relevant to determine the heteroplasmy levels within individual cells to understand the mechanism of clonal expansion. Heteroplasmy is reflected in a mosaic distribution of cytochrome c oxidase (COX)-deficient muscle fibers. We applied droplet digital PCR (ddPCR) to single muscle fibers collected by laser-capture microdissection (LCM) from muscle biopsies of patients with different paradigms of mitochondrial disease, characterized by the accumulation of single or multiple mtDNA deletions. By combining these two sensitive approaches, ddPCR and LCM, we document different models of clonal expansion in patients with single and multiple mtDNA deletions, implicating different mechanisms and time points for the development of COX deficiency in these molecularly distinct mitochondrial cytopathies.
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.30472
dc.identifier.eissn2045-2322
dc.identifier.issn2045-2322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283111
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41598-018-30143-z
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectBiopsy
dc.subjectDNA, Mitochondrial
dc.subjectElectron Transport Complex IV
dc.subjectFemale
dc.subjectGTP Phosphohydrolases
dc.subjectGene Dosage
dc.subjectGenes, Recessive
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectMuscle Cells
dc.subjectMuscle Fibers, Skeletal
dc.subjectMutation
dc.subjectOxidative Phosphorylation
dc.subjectPolymerase Chain Reaction
dc.subjectReproducibility of Results
dc.subjectSequence Deletion
dc.subjectSuccinate Dehydrogenase
dc.subjectYoung Adult
dc.titleClonal expansion of mtDNA deletions: different disease models assessed by digital droplet PCR in single muscle cells.
dc.typeArticle
dcterms.dateAccepted2018-07-18
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameSci Rep
prism.startingPage11682
prism.volume8
pubs.funder-project-idWellcome Trust (109915_A_15_Z)
pubs.funder-project-idMedical Research Council (MR/N025431/2)
rioxxterms.licenseref.startdate2018-08-03
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41598-018-30143-z

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