This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed project will investigate the patterns of gene expression, and associated molecular events, in a sample of boys with genetic MR as well as in a group of subjects with severe MR of unknown, but likely, genetic origin (UMR). We primarily intend to identify profiles of gene expression that are common to both major genetic disorders associated with MR, specifically Down syndrome (DS), Fragile X syndrome (FraX), and non-syndromix X-linked MR (XLMR), and UMR. We hypothesize that these patterns will include abnormalities in key signaling pathways that link synaptic activity and neuronal gene expression, and that these pathways could eventually be targeted for diagnostic and therapeutic purposes. In addition, by preliminary molecular-phenotypical correlations, we intend to both classify subjects with UMR and determine the specific contributions of sbnormally-expressed genes to (the variance) of certain aspects of the phenotype of the MR groups under study. Molecular profiles will be studied on peripheral lymphocytes and lymphoblastoid cell lines using microarray and immunoblotting assays for histone posttranslational modifications. Phenotypical characterizations will include detailed family and clinical history, physical examination, and comprehensive neurobehavioral evaluation. The protcol intends to recruit 20 male subjects, ages 5-10 years, with severe MR (FSIQ: 20-50) from each DS, FraX, XLMR, and UMR groups, and 20 age/sex matched normal controls, over a 12 -18 month period. Analyses of molecular pateerns, which will include custom-designed databases and bioinformatics approaches, will be conducted throughout the two-year study period. We postulate that this study will demonstrate that patients with UMR share abnormalities in signal transduction with subjects with DS, FraX, and XLMR and that the severity and otehr aspects of their phenotype can be linked to specific genes and patterns of global histone modifications.
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