Genetic and epigenetic defects in mental retardation.

Mental retardation (MR) is a highly diverse group of cognitive disorders. The high incidence of MR, 2-3% in most populations, and the high burden for families and society makes this condition one of the major unsolved problems in modern medicine. Gene defects account for about half of all patients and more than 300 genes are known that, when mutated, lead to cognitive dysfunction. A strikingly high number of these MR genes encode regulators of chromatin structure and of chromatin-mediated transcription regulation. Prominent examples of these include the methyl CpG-binding protein MECP2, the H3K4 demethylase JARID1c and the H3K9 histone methyltransferase EHMT1. Moreover, several of these epigenetic MR proteins have been found to directly interact with one another or act in complexes that regulate the local chromatin structure at target genes that are key to normal neuronal activities. Thus, it appears that the function of individual MR genes converges to similar biological processes. More detailed knowledge about the altered DNA methylation and histone marks that are introduced by epigenetic gene mutations as well as more insight into neuronal genes whose expression is disrupted by this will provide a rationale for therapeutic strategies.