ARX-dependent KDM5C defects are associated to X-linked intellectual disability and epilepsy.

Intellectual Disability (ID) and Epilepsy often occur together with a dramatic impact on the development and quality of life of the affected children. PolyAlanine expansion mutations of Aristaless-related homeobox gene (ARX) cause a spectrum of X-chromosome phenotypes with ID (XLID) and various forms of malignant paediatric epilepsy. We here present that lysine (K)-specific demethylase 5C (KDM5C/JARID1C/SMCX), a known XLID gene involved in chromatin remodeling, is an ARX-dependent target, demonstrating a functional link between these two XLID/Epilepsy genes. Combining luciferase reporter and DNA binding assays, we reveal that ARX directly binds a CNE in the 5' region of KDM5C. Our investigation into the functional properties of ARX with PolyAlanine expansions have demonstrated that changes in the repeat units cause a decreased trans-activating activity and a reduced, but not abolished, binding to the KDM5C regulatory region. In the Arx KO ES disease model, a decreased level of Kdm5C mRNA and protein has been shown to be associated with an increased level of H3K4me3, a defect that could compromise cyclical rounds of methylation-demethylation and consequently the genes in DNA "off" and "on". These data suggest that ARX and KDM5C may be functionally connected in specific neuronal paths, which once identified, could facilitate the dissection of the peculiar neurophenotypes observed in XLID and Epilepsy patients. Overall, a role for chromatin packaging in ARX diseases is an attractive hypothesis as it expands our horizons of the modes of PolyAlanine pathogenesis, however further study it required.