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Front Mol Neurosci. 2018 Apr 4;11:104. doi: 10.3389/fnmol.2018.00104. eCollection 2018.

Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability.

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Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States.
Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC, United States.
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States.
Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.
Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States.


Intellectual disability (ID) affects up to 2% of the population world-wide and often coincides with other neurological conditions such as autism spectrum disorders. Mutations in KDM5C cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID. KDM5C encodes a histone demethylase for di- and tri-methylated histone H3 lysine 4 (H3K4me2/3), which are enriched in transcriptionally engaged promoter regions. KDM5C regulates gene transcription; however, it remains unknown whether removal of H3K4me is fully responsible for KDM5C-mediated gene regulation. Most mutations functionally tested to date result in reduced enzymatic activity of KDM5C, indicating loss of demethylase function as the primary mechanism underlying MRXSCJ. Here, we report a novel KDM5C mutation, R1115H, identified in an individual displaying MRXSCJ-like symptoms. The carrier mother's cells exhibited a highly skewed X-inactivation pattern. The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability. However, when overexpressed in post-mitotic neurons, KDM5C-R1115H failed to fully suppress expression of target genes, while the mutant also affected expression of a distinct set of genes compared to KDM5C-wildtype. These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient.


KDM5C/SMCX/JARID1C; X-linked intellectual disability; autism spectrum disorders; chromatin; histone demethylase; mutation analysis; neuroepigenetics

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