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dc.contributor.authorMartinez Lyons, Anabelen
dc.contributor.authorArdissone, Annaen
dc.contributor.authorReyes Tellez, Aurelioen
dc.contributor.authorRobinson, Alanen
dc.contributor.authorMoroni, Isabellaen
dc.contributor.authorGhezzi, Danieleen
dc.contributor.authorFernandez-Vizarra, Erikaen
dc.contributor.authorZeviani, Massimoen
dc.date.accessioned2017-08-16T08:27:06Z
dc.date.available2017-08-16T08:27:06Z
dc.date.issued2016-11-23en
dc.identifier.issn1468-6244
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/266442
dc.description.abstractBACKGROUND: Assembly of cytochrome c oxidase (COX, complex IV, cIV), the terminal component of the mitochondrial respiratory chain, is assisted by several factors, most of which are conserved from yeast to humans. However, some of them, including COA7, are found in humans but not in yeast. COA7 is a 231aa-long mitochondrial protein present in animals, containing five Sel1-like tetratricopeptide repeat sequences, which are likely to interact with partner proteins. METHODS: Whole exome sequencing was carried out on a 19 year old woman, affected by early onset, progressive severe ataxia and peripheral neuropathy, mild cognitive impairment and a cavitating leukodystrophy of the brain with spinal cord hypotrophy. Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle. Mitochondrial localization studies were carried out in isolated mitochondria and mitoplasts from immortalized control human fibroblasts. RESULTS: We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C, and a maternal c.287+1G>T variants. Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient fibroblasts led to the recovery of the defect in COX activity and restoration of normal COX amount. In mitochondrial localization experiments, COA7 behaved as the soluble matrix protein Citrate Synthase. CONCLUSIONS: We report here the first patient carrying pathogenic mutations of COA7, causative of isolated COX deficiency and progressive neurological impairment. We also show that COA7 is a soluble protein localized to the matrix, rather than in the intermembrane space as previously suggested.
dc.description.sponsorshipSupported by Telethon-Italy grant GGP15041 (to DG); Telethon-Italy Network of Genetic Biobank grant GTB12001J; ERC advanced grant ERC FP7-322424 (to MZ). MRC QQR grant MC_UP_1002/1.
dc.languageengen
dc.language.isoenen
dc.publisherBMJ Publishing Group
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectCOX assemblyen
dc.subjectMolecular geneticsen
dc.subjectNeurologyen
dc.subjectmitochondrial diseaseen
dc.subjectmitochondrial respiratory chaixnen
dc.subjectAmino Acid Sequenceen
dc.subjectCytochrome-c Oxidase Deficiencyen
dc.subjectDNA Mutational Analysisen
dc.subjectFemaleen
dc.subjectHumansen
dc.subjectLeukoencephalopathiesen
dc.subjectMitochondriaen
dc.subjectMitochondrial Proteinsen
dc.subjectMutationen
dc.subjectSequence Alignmenten
dc.subjectYoung Adulten
dc.titleCOA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.en
dc.typeArticle
prism.endingPage849
prism.issueIdentifier12en
prism.publicationDate2016en
prism.publicationNameJournal of Medical Geneticsen
prism.startingPage846
prism.volume53en
dc.identifier.doi10.17863/CAM.10003
dcterms.dateAccepted2016-08-30en
rioxxterms.versionofrecord10.1136/jmedgenet-2016-104194en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc/4.0/en
rioxxterms.licenseref.startdate2016-11-23en
dc.contributor.orcidReyes Tellez, Aurelio [0000-0003-2876-2202]
dc.contributor.orcidRobinson, Alan [0000-0001-9943-0059]
dc.identifier.eissn1468-6244
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_U105674181)
pubs.funder-project-idEuropean Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
pubs.funder-project-idMRC (MC_UP_1002/1)
cam.issuedOnline2016-09-28en
dc.identifier.urlhttps://jmg.bmj.com/content/53/12/846en


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