Isolation and characterization of candidate genes for Down syndrome

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To isolate genes potentially involved in the pathogenesis of Down syndrome, we have performed exon trapping experiments using a series of cosmid clones derived from the "Down syndrome critical region (DSCR)" on chromosome 21q22.1-q22.2. To date, we have isolated 155 different exons. These include exons derived from known human genes (ERG,HCS,CAF-1) and exons that were homologous to human cDNA fragments or cDNAs from other species (Drosophila single-minded (sim), Drosophila minibrain (mnb), and mouse Girk2 genes). Among the three genes for which human homologs were identified, the Drosophila sim gene functions as a master developmental regulator which instructs a specific subset of neuroectodermal cells to develop into central nervous system midline cells, the Drosophila mnb gene encodes a serine/threonine kinase that is essential for the neuroblast proliferation during neurogenesis, and the mouse Girk2 gene encodes a G-protein coupled inward rectifier potassium channel for which the cause of a weaver mutant was reported. Thus the identification of these human homologs (SIM2, MNB,and GIRK2) from the DSCR is quite intriguing. We isolated the cDNA clones encoding SIM2 and MNB proteins. We further demonstrated diencephalon-specific expression of SIM2 mRNA in early stages of mouse embryos. The MNB mRNA is expressed in various tissues including fetal and adult brains. Ninety-five exons including those of SIM2, HCS,MNB,GIRK2, ERG genes as well as newly reported genes for TPRD and Kir1.3 (inward rectifier potassium channel) have been mapped on an EcoRI restricition map of the DSCR which was constructed from 4-Mb cosmid/PAC contigs. These studies should yield additional candidate genes for the pathogenesis of Down syndrome.