Down Syndrome, Lifespan Development and Gene Expression

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

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Abstract

Down syndrome (DS), caused by trisomy 21 (+21), is a complex neurodevelopmental disorder that accounts for a high proportion of mental retardation, and which is associated with a form of early-onset Alzheimer's disease. DS results from an abnormality of gene dosage, but the specific genes whose abnormal expression leads to each of its phenotypic features are largely unknown. Some of these genes must be on chromosome 21, but genes on other chromosomes may be dysregulated because of +21. Importantly, gene expression programs altered by +21 are likely to differ by tissue and developmental stage. Microarray-based analysis is a well-standardized and economical high-throughput method for assessing differences in gene expression. Important descriptive information from such studies can be vetted in functional assays in vitro and in vivo, as well as in genetic-epidemiological studies. Previously, as part of a collaboration established with the Institute for Basic Research in Developmental Disabilities Aging Research Program (W. Silverman, Head) in a project investigating the genotypic and phenotypic characteristics of adults with DS, 65 and older, we successfully employed this strategy to compare gene expression in fibroblasts and amniocytes with +21 vs. matched normal control cells, and to investigate the function of agene with significant differential expression, MXA. Our findings were informative for general models of gene dysregulation in +21. However, they may not be directly pertinent to the neurodevelopmental and cognitive aspects of the DS phenotype, which are likely due to dysregulation of other genes. To address these aspects, we now propose to extend our work to the analysis of specific brain regions, both in human DS spanning a range of ages, and in a widely used mouse model of DS, the Ts65Dn strain.