title: Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity.
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.
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA, Division of Newborn Medicine, Boston Children's Hospital, MA 02115, USA.
authors: Emily
authors: E
authors: Brookes
authors: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA, Division of Newborn Medicine, Boston Children's Hospital, MA 02115, USA.
authors: Benoit
authors: B
authors: Laurent
authors: Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia, Department of Pediatrics, University of Tartu, Tartu, Estonia.
authors: Katrin
authors: K
authors: Õunap
authors: School of Paediatrics and Reproductive Health and Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors: Renee
authors: R
authors: Carroll
authors: Department of Pediatrics, Geisel School of Medicine, Lebanon, NH 03756, USA.
authors: John B
authors: JB
authors: Moeschler
authors: GOLD NSW, Hunter Genetics, Newcastle, Australia and.
authors: Michael
authors: M
authors: Field
authors: JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors: Charles E
authors: CE
authors: Schwartz
authors: School of Paediatrics and Reproductive Health and Robinson Institute, The University of Adelaide, Adelaide, SA 5000, Australia.
authors: Jozef
authors: J
authors: Gecz
authors: 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.
authors: Yang
authors: Y
authors: Shi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002843:Chromatin / Q000201:enzymology / Q000235:genetics; D004795:Enzyme Stability; D005260:Female; D050172:Genes, X-Linked; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008745:Methylation; D009154:Mutation; D055815:Young Adult
chemical_list: D002843:Chromatin; D006657:Histones; D056466:Histone Demethylases; C086877:KDM5C protein, human