Histone methylation-demethylation defects in forms of Intellectual Disability and Refractory Epilepsy

Mistakes in histone methylation-demethylation rounds have been directly involved in several forms of Intellectual Disability (ID) with Epilepsy and/or Refractory Epilepsy (RE). Lysine-specific demethylase 5C (KDM5C) is an X-linked gene, which encodes a chromatin JmjC eraser with H3K4me2/3 demethylase activity. KDM5C is frequently mutated in a spectrum of X-linked ID (XLID) and/or RE. It functions as a transcriptional repressor that is critical for transition of neural progenitors to neurons. We identified a disease path, linking functionally KDM5C to another XLID/Epilepsy gene, encoding the homeotic transcription factor ARX, whose mutations impair severely KDM5C transcript regulation.Ongoing efforts will allow us to identify druggable hallmarks that could open up towards the exploitation of potential strategies to treat the growing group of ID and RE diseases caused by defects in chromatin and/or transcriptional regulators.