26 At a molecular level, the mutation has effects on the pattern of genomic
methylation, consistent with the role of ATRX in chromatin remodeling.27 The pleiotropic effects of mutations in MECP2 and ATRX could result from the regulated expression of a restricted class of genes. Investigation of a syndromic MR condition, CLS, has led to the discovery of the involvement of another signaling pathway in cognitive impairment, Inhibitors,research,lifescience,medical namely the MAPK-activated signaling pathway (MAPK for mitogen-activated protein kinase). CLS is characterized by severe psychomotor retardation, facial and digital physical anomalies, and progressive skeletal deformation. The disorder was mapped by linkage to the region Xp22.2 and mutations discovered in a positional candidate gene RSK2 (also known as RPS6KA3).28 RSK2 mediates growth factor induction of cyclic adenosine monophosphate Inhibitors,research,lifescience,medical response element-binding protein (CREB) phosphorylation, as part of a signaling pathway whereby Ras-MAPK and Ras signals are transmitted to the nucleus to activate gene
expression. Remarkably, mutations in RSK2 give rise to nonsyndromic MR: patients in an XLMR family with neither facial, digital, nor skeletal anomalies compatible with CLS, but with mild MR, have been found to have a mutation in exon 14 of the gene, resulting in a conservative amino acid change.17 The Inhibitors,research,lifescience,medical pathogenesis Inhibitors,research,lifescience,medical remains obscure. Segmental aneusomy syndromes A number of genetic conditions associated with intellectual disability have been found to be due to small chromosomal
deletions or duplications (typically less than 5 megabases) and are known as segmental aneusomy syndromes (sec Tabic II).29 The small size Inhibitors,research,lifescience,medical of some of the regions has enabled a search for dosage-sensitive genes. However, in order to prove that a deleted gene is Rucaparib mouse indeed dosage-sensitive, it has been necessary to find families with point mutations in the gene that segregate with intellectual disability. This has been achieved with Rubinstein-Taybi syndrome (characterized by abnormal craniofacial features, broad thumbs, and intellectual disability), which can arise from monosomy of a small region in 16pl3.3.30 The responsible gene expresses the CREB-binding protein (CBP).31 Unfortunately, this approach has not been so successful Rebamipide for other segmental aneusomies. Williams-Beuren syndrome is a neurodevelopmental disorder characterized by congenital heart disease, infantile hypercalcemia, dysmorphic facial features, and cognitive disability. It is due to haploinsufficiency of genes in the region 7q11.32 It is known that mutations affecting the elastin gene give rise to the supravalvular aortic stenosis, but there are still at least 15 candidate genes that could be involved in the unusual cognitive profile of the syndrome.