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Hum Mol Genet. 2015 May 15;24(10):2861-72. doi: 10.1093/hmg/ddv046. Epub 2015 Feb 9.

Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA, Division of Newborn Medicine, Boston Children's Hospital, MA 02115, USA.
2
Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia, Department of Pediatrics, University of Tartu, Tartu, Estonia.
3
School of Paediatrics and Reproductive Health and Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
4
Department of Pediatrics, Geisel School of Medicine, Lebanon, NH 03756, USA.
5
GOLD NSW, Hunter Genetics, Newcastle, Australia and.
6
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
7
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA, Division of Newborn Medicine, Boston Children's Hospital, MA 02115, USA, yshi@hms.harvard.edu.

Abstract

Mutations in KDM5C are an important cause of X-linked intellectual disability in males. KDM5C 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 KDM5C expression, stability and catalytic activity. We report and characterize a novel nonsense mutation, c.3223delG (p.V1075Yfs*2), which leads to loss of KDM5C protein. We also characterize two KDM5C missense mutations, c.1439C>T (p.P480L) and c.1204G>T (p.D402Y) that are compatible with protein production, but compromise stability and enzymatic activity. Finally, we demonstrate that a c.2T>C mutation in the translation initiation codon of KDM5C results in translation re-start and production of a N-terminally truncated protein (p.M1_E165del) 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 KDM5C 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.

PMID:
25666439
PMCID:
PMC4406297
DOI:
10.1093/hmg/ddv046
[Indexed for MEDLINE]
Free PMC Article

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