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dc.contributor.authorBrookes, E.en
dc.contributor.authorLaurent, B.en
dc.contributor.authorÕunap, K.en
dc.contributor.authorCarroll, R.en
dc.contributor.authorMoeschler, J.en
dc.contributor.authorField, M.en
dc.contributor.authorSchwartz, C.en
dc.contributor.authorGecz, J.en
dc.contributor.authorShi, Y.en
dc.identifier.citationHuman Molecular Genetics, 2015; 24(10):2861-2872en
dc.descriptionFirst published online: February 9, 2015en
dc.description.abstractMutations in KDM, C are an important cause of X-linked intellectual disability in males. KDM, C encodes a histone demethylase, suggesting that alterations in chromatin landscape may contribute to disease. We used primary patient cells and biochemical approaches to investigate the effects of patient mutations on KDM, C expression, stability and catalytic activity. We report and characterize a novel nonsense mutation, c., delG, p.V, Yfs, which leads to loss of KDM, C protein. We also characterize two KDM, C missense mutations, c., C, T, p.P, L, and c., G, T, p.D, Y, that are compatible with protein production, but compromise stability and enzymatic activity. Finally, we demonstrate that a c., T, C mutation in the translation initiation codon of KDM, C results in translation re-start and production of a N-terminally truncated protein, p.M, E, del, that is unstable and lacks detectable demethylase activity. Patient fibroblasts do not show global changes in histone methylation but we identify several up-regulated genes, suggesting local changes in chromatin conformation and gene expression. This thorough examination of KDM, C patient mutations demonstrates the utility of examining the molecular consequences of patient mutations on several levels, ranging from enzyme production to catalytic activity, when assessing the functional outcomes of intellectual disability mutations.en
dc.description.statementofresponsibilityEmily Brookes, Benoit Laurent, Katrin Õunap, Renee Carroll, John B. Moeschler, Michael Field, Charles E. Schwartz, Jozef Gecz, and Yang Shien
dc.publisherOxford University Press (OUP)en
dc.rights© The Author 2015. Published by Oxford University Press. All rights reserveden
dc.subjectChromatin; Humans; Histones; Enzyme Stability; Methylation; Mutation; Adolescent; Adult; Aged; Child; Infant; Female; Male; Genes, X-Linked; Young Adult; Histone Demethylases; Intellectual Disabilityen
dc.titleMutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activityen
dc.typeJournal articleen
pubs.library.collectionPaediatrics publicationsen
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

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