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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.

Author information

1
Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States.
2
Diagnostic Laboratory, Greenwood Genetic Center, Greenwood, SC, United States.
3
Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States.
4
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States.
5
Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States.
6
Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States.

Abstract

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.

KEYWORDS:

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

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