Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/91774
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Type: Journal article
Title: Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity
Author: Brookes, E.
Laurent, B.
Õunap, K.
Carroll, R.
Moeschler, J.
Field, M.
Schwartz, C.
Gecz, J.
Shi, Y.
Citation: Human Molecular Genetics, 2015; 24(10):2861-2872
Publisher: Oxford University Press (OUP)
Issue Date: 2015
ISSN: 0964-6906
1460-2083
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Responsibility: 
Emily Brookes, Benoit Laurent, Katrin Õunap, Renee Carroll, John B. Moeschler, Michael Field, Charles E. Schwartz, Jozef Gecz, and Yang Shi
Abstract: Mutations 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.
Keywords: Chromatin; Humans; Histones; Enzyme Stability; Methylation; Mutation; Adolescent; Adult; Aged; Child; Infant; Female; Male; Genes, X-Linked; Young Adult; Histone Demethylases; Intellectual Disability
Description: First published online: February 9, 2015
Rights: © The Author 2015. Published by Oxford University Press. All rights reserved
RMID: 0030022638
DOI: 10.1093/hmg/ddv046
Appears in Collections:Paediatrics publications

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