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dc.contributor.authorLanger, Yeshaya
dc.contributor.authorAran, Adi
dc.contributor.authorGulsuner, Suleyman
dc.contributor.authorAbu Libdeh, Bassam
dc.contributor.authorRenbaum, Paul
dc.contributor.authorBrunetti, Dario
dc.contributor.authorTeixeira, Pedro-Filipe
dc.contributor.authorWalsh, Tom
dc.contributor.authorZeligson, Sharon
dc.contributor.authorRuotolo, Roberta
dc.contributor.authorBeeri, Rachel
dc.contributor.authorDweikat, Imad
dc.contributor.authorShahrour, Maher
dc.contributor.authorWeinberg-Shukron, Ariella
dc.contributor.authorZahdeh, Fouad
dc.contributor.authorBaruffini, Enrico
dc.contributor.authorGlaser, Elzbieta
dc.contributor.authorKing, Mary-Claire
dc.contributor.authorLevy-Lahad, Ephrat
dc.contributor.authorZeviani, Massimo
dc.contributor.authorSegel, Reeval
dc.date.accessioned2018-11-21T10:07:54Z
dc.date.available2018-11-21T10:07:54Z
dc.date.issued2018-09
dc.identifier.issn0022-2593
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285560
dc.description.abstractOBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids. CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherBMJ
dc.subjectCerebellum
dc.subjectMitochondria
dc.subjectHumans
dc.subjectCerebellar Diseases
dc.subjectAtrophy
dc.subjectMetalloendopeptidases
dc.subjectMitochondrial Proteins
dc.subjectPedigree
dc.subjectAge of Onset
dc.subjectAdolescent
dc.subjectChild
dc.subjectArabs
dc.subjectMale
dc.subjectYoung Adult
dc.subjectWhole Genome Sequencing
dc.subjectWhole Exome Sequencing
dc.subjectLoss of Function Mutation
dc.titleMitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy.
dc.typeArticle
prism.endingPage606
prism.issueIdentifier9
prism.publicationDate2018
prism.publicationNameJ Med Genet
prism.startingPage599
prism.volume55
dc.identifier.doi10.17863/CAM.32916
dcterms.dateAccepted2018-04-10
rioxxterms.versionofrecord10.1136/jmedgenet-2018-105330
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidBrunetti, Dario [0000-0002-2740-9370]
dc.contributor.orcidKing, Mary-Claire [0000-0001-9426-1743]
dc.contributor.orcidZeviani, Massimo [0000-0002-9067-5508]
dc.identifier.eissn1468-6244
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_EX_MR/P007031/1)
pubs.funder-project-idEuropean Research Council (322424)
cam.issuedOnline2018-05-15


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