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dc.contributor.authorARDISSONE, Anna
dc.contributor.authorTekturk, Pınar
dc.contributor.authorTAYLOR, Robert W.
dc.contributor.authorPROKISCH, Holger
dc.contributor.authorUZIEL, Graziella
dc.contributor.authorMORONI, Isabella
dc.contributor.authorYapici, Zuhal
dc.contributor.authorBERTINI, Enrico
dc.contributor.authorvan der Knaap, Marjo S.
dc.contributor.authorGHEZZI, Daniele
dc.contributor.authorZEVIANI, Massimo
dc.contributor.authorMELCHIONDA, Laura
dc.contributor.authorHAACK, Tobias B.
dc.contributor.authorHARDY, Steven
dc.contributor.authorAbbink, Truus E. M.
dc.contributor.authorFERNANDEZ-VIZARRA, Erika
dc.contributor.authorLAMANTEA, Eleonora
dc.contributor.authorMARCHET, Silvia
dc.contributor.authorMORANDI, Lucia
dc.contributor.authorMOGGIO, Maurizio
dc.contributor.authorCARROZZO, Rosalba
dc.contributor.authorTORRACO, Alessandra
dc.contributor.authorDIODATO, Daria
dc.contributor.authorSTROM, Tim M.
dc.contributor.authorMEITINGER, Thomas
dc.contributor.authorAL-MURSHEDI, Fathiya
dc.contributor.authorSTEVENS, Rene
dc.contributor.authorRODENBURG, Richard J.
dc.contributor.authorLAMPERTI, Costanza
dc.date.accessioned2021-03-02T20:13:34Z
dc.date.available2021-03-02T20:13:34Z
dc.date.issued2014
dc.identifier.citationMELCHIONDA L., HAACK T. B. , HARDY S., Abbink T. E. M. , FERNANDEZ-VIZARRA E., LAMANTEA E., MARCHET S., MORANDI L., MOGGIO M., CARROZZO R., et al., "Mutations in APOPT1, Encoding a Mitochondria! Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency", AMERICAN JOURNAL OF HUMAN GENETICS, cilt.95, sa.3, ss.315-325, 2014
dc.identifier.issn0002-9297
dc.identifier.otherav_00fe21c9-fbb5-4cfe-adfb-9038f837558e
dc.identifier.othervv_1032021
dc.identifier.urihttp://hdl.handle.net/20.500.12627/6646
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2014.08.003
dc.description.abstractCytochrome c oxidase (COX) deficiency is a: frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein. We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation.
dc.language.isoeng
dc.subjectYaşam Bilimleri
dc.subjectTemel Bilimler
dc.subjectMoleküler Biyoloji ve Genetik
dc.subjectTıp
dc.subjectDahili Tıp Bilimleri
dc.subjectTıbbi Genetik
dc.subjectGENETİK VE HAYAT
dc.subjectMoleküler Biyoloji ve Genetik
dc.subjectYaşam Bilimleri (LIFE)
dc.subjectSağlık Bilimleri
dc.titleMutations in APOPT1, Encoding a Mitochondria! Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency
dc.typeMakale
dc.relation.journalAMERICAN JOURNAL OF HUMAN GENETICS
dc.contributor.departmentIRCCS Bambino Gesu , ,
dc.identifier.volume95
dc.identifier.issue3
dc.identifier.startpage315
dc.identifier.endpage325
dc.contributor.firstauthorID52890


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