BRIDGING GENES AND HEART DISEASE IN DOWNS SYNDROME

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Down syndrome (DS) is a major cause of congenital heart disease (CHD), of which most is related to defective morphogenesis of the endocardial cushions ( EC). Although the embryologic processes underlying cushion morphogenesis are elegantly described, the signalling pathways that lead from genes to defects are largely unknown. The ultimate goal of the research described in this proposal is to define the gen(s) responsible for DS-CHD, to define its role in cushion morphogenesis and to provide models in which to modify its expression. Previous work by this group has defined a DS-CHD region based on human and mouse models and has generated a sequence ready contig, with 300 kb of finished sequence and the remainder by 1/1999, and transcriptional map of 30 cDNAs in the 4 Mb candidate region on chromosome 21, as well as sequencing and characterization of a likely candidate., DS-CAM. Analysis of the human and mouse DS CAM clones reveal a highly conserved novel class of cell adhesion molecules (CAM) of the Ig superfamily with ten Ig2 and six fibronectin domains and both extracellular and transmembrane forms. Expression in the endocardial cushions, neurons, neural crest and other sites of epithelial induction, promoter sites for known cardiogenic transcription factors (Mef2), combine with its map position with a small DS-CHD region, to make DS Cam a likely candidate. Not all mouse models of partial trisomy 16 including the DS-CHD region develop heart disease. To elucidate the role of DS-CAM in DS-CHD, the role of compartment specific expression (myocardium, endocardium, neural crest), mouse models of DS-CAM compartment specific over-expression (myocardium, endocardium, neural crest), mouse models of DS-CAM compartment specific over-expression and lack of expression will be generated as will models to address the possible contribution of the chromosome 21 gene for collagen VIa1/a2 located on MMU 10. We propose 4 aims; I and II narrow the region and examine human expression; III-V (in collaboration with the UCSD Mouse Core and Project 1) use mouse models to test the hypothesis that DS-CAM is the gene for DS-CHD, and VI defines the remainder of genes in the DS-CHD region. By defining the role of DS-CAM and its regulatory and interacting molecules, this work will provide the candidate causes for isolated AVSD, VSD, ASD and PS as well as other forms of monogenic CHD. Understanding DS CAM will provide insight into pathways on normal EC morphogenesis and their maldevelopment that cause the majority of deaths due to congenital anomalies.