Association of phenotypic abnormalities of Down syndrome with an imbalance of genes on chromosome 21.

The phenotype of the brain in Down syndrome is different from that of a normal child both in its reduced size and altered gyral configuration. Underlying the mental retardation are neuronal abnormalities, including alterations of cortical lamination, reduced dendritic ramifications, and diminished synaptic formation. However, cholinergic enzymes such as choline acetyl transferase and acetyl cholinesterase have shown no abnormalities in young children with Down syndrome. The pace of dendritic maturation is altered in Down syndrome. In infancy, the normal dendritic tree continuously expands; in Down syndrome, at 4 months of age, the neurons show a relatively expanded tree, but during the first year, the dendrites stop growing and become atrophic relative to control neurons. To relate these phenotypic alterations to chromosome 21, we examined the gene products of several genes localized to chromosome 21. Identification of such genes and determination of their gene product allow the production of specific antibodies and the identification, through immunohistochemical techniques, of the expression of these proteins in both normal development and Down syndrome. Specifically, the localization and appearance during development of proteins such as S100 beta, beta A4-amyloid, superoxide dismutase, and OK-2 are providing links between genotype and phenotype. S100 beta protein is of particular interest because of its effect in vitro on neuritic outgrowth and its increased expression in the temporal lobe in Down syndrome. The brains of transgenic mice bearing multiple copies of the human S100 gene show some comparable changes to those in Down syndrome. These experimental approaches provide the means for better understanding the cellular and molecular basis for the mental retardation in Down syndrome.