Kdm6a Mutation Deregulates Translation and Nonsense Mediated Mrna Decay Pathways in Intellectual Disability Patients

Background and aim: intellectual disability (id) is the most common neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behavior, including conceptual, social and practical skills; arising prior to age 18. in recent years, many causative id mutations have been identified in genes coding for proteins involved in chromatin remodeling. a recent study reported 13.3% of id-related genes involved in epigenetic transcription regulation. kdm6a, lysine-specific demethylase 6 a, also known as utx, is a histone remodeler which mediates removal of repressive trimethylation of h3k27 to establish transcriptionally permissive chromatin. mutations in kdm6a results in syndromic and non-syndromic forms of id.methods: in this study, we performed transcriptome analysis in order to identify biological processes and molecular pathways underlying id disease, using rna-seq technique which has numerous applications within the scope of transcriptome analysis including: quantification of gene expression,detection of differentially expressed genes, identification of novel mrna isoforms, and of alternative‐ splicing events.results: we examined a family with mutation in kdm6a. of all 591 differentially expressed genes (q-value< 0.05, fold change >1.5) between patients and controls, 428 genes were upregulated and 163 genes were downregulated. based on gene ontology analysis, the most significant altered pathways were peptide chain elongation, eukaryotic translation and elongation, nonsense mediated mrna decay independent of the exon junction complex, formation of a pool of free 40s subunits (small subunit of ribosome) and acetylation.conclusion: our results suggest klf4, gfi1 and yy1 as upstream regulators which their role in id is firmly established. these findings may provide important clues toward deciphering id disease.