DSCAM - A NOVEL MEMBER OF THE IMMUNOGLOBULIN SUPERFAMILY MAPS IN A DOWN-SYNDROME REGION AND IS INVOLVED IN THE DEVELOPMENT OF THE NERVOUS-SYSTEM

Down syndrome (DS), a major cause of mental retardation, is characteri zed by subtle abnormalities of cortical neuroanatomy, neurochemistry a nd function, Recent work has shown that chromosome band 21q22 is criti cal for many of the neurological phenotypes of DS, A gene, DSCAM (Down syndrome cell adhesion molecule), has now been isolated from chromoso me band 21q22.2-22.3, Homology searches indicate that the putative DSC AM protein is a novel member of the immunoglobulin (Ig) superfamily th at represents a new class of neural cell adhesion molecules, The seque nce of cDNAs indicates alternative splicing and predicts two protein i soforms, both containing 10 Ig-C2 domains, with nine at the N-terminus and the tenth located between domains 4 and 5 of the following array of six fibronectin III domains, with or without the following transmem brane and intracellular domains, Northern analyses reveals the transcr ipts of 9.7, 8.5 and 7.6 kb primarily in brain. These transcripts are differentially expressed in substructures of the adult brain, Tissue i n situ hybridization analyses of a mouse homolog of the DSCAM gene rev ealed broad expression within the nervous system at the time of neuron al differentiation in the neural tube, cortex, hippocampus, medulla, s pinal cord and most neural crest-derived tissues, Given its location o n chromosome 21, its specific expression in the central nervous system and neural crest, and the homologies to molecules involved in neural migration, differentiation, and synaptic function, we propose that DSC AM is involved in neural differentiation and contributes to the centra l and peripheral nervous system defects in DS.