Gene Expression and Genetic Mental Retardation (MR)

Principal Investigator: Rebecca Vaurio

This project investigates the patterns of gene expression, and associated molecular events, in a sample of boys with genetic mental retardation (MR). We intend to identify profiles of gene expression that are common to the two major genetic disorders associated with MR, specifically Down syndrome (DS) and Fragile X syndrome (FraX). 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. Molecular profiles will be studied on peripheral lymphocytes and lymphoblastoid cell lines and serum using microarrays for RNA, immunoblotting assays for histone posttranslational modifications, and ELISA for four key growth factors/neurotrophins, respectively. Phenotypical characterizations will include detailed family and clinical history, physical examination, and comprehensive neurobehavioral evaluation. Over a period of 12-18 months, 40 male subjects with DS or FraX (20 subjects with each condition), ages 5-10 years, and 80 of their parents (ages 18-99 years) will be recruited for this study. Twenty age/sex-matched normal controls will provide reference values for the molecular analyses, which will include custom-designed databases and bioinformatics approaches and will be conducted throughout the two-year study period. We postulate that this study will demonstrate common neuronal signaling abnormalities to both DS and FraX, and that the severity and other aspects of the subjects' neurobehavioral phenotype can be linked to specific genes and patterns of global histone modifications.