Finding new connections in the transcriptional regulation of Lysine-specific demethylase 5C (KDM5C) a disease gene involved in syndromic and non-syndromic XLID.

X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Disease mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID disorders. Mutations in Lysine-specific demethylase 5C (KDM5C) gene, located at Xp11.22, have been reported as an important cause of both syndromic and non-syndromic X-linked intellectual disability (XLID) in males. KDM5C is a chromatin remodelling regulator with histone demethylase activity for di- and trimethylated histone 3 lysine 4 (H3K4me2 and H3K4me3), acting as transcriptional repressor during brain development and neuronal maturation. With Regulatory Element-1-Silencing Transcription factor (REST), a critical regulator of the spatio-temporal transition of neural progenitors to neurons, KDM5C co-occupies the promoters of a subset of REST target genes. We recently 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.Expanding our study, we analysed two additional XLID proteins that also bind the KDM5C promoter. Our findings open new perspectives towards the exploitation of rational strategies to treat the growing group of ID and cognition diseases that are caused by chromatin and/or transcriptional defects.