Down Syndrome is the most common genetic cause of major mental retardation in the United States, affecting approximately 300,000 individuals and their families. In addition to mental retardation, individuals with Down Syndrome are also subject to many other developmental problems. For example, roughly half have characteristic congenital heart disease. They have a 20 to 40-fold increased risk of developing leukemia. As they age, they are likely to develop Alzheimer Disease. Down Syndrome is caused by the presence of an extra copy of chromosome 21 or rarely an extra copy of a smaller region of chromosome 21. Moreover, other aneuploidies of regions of chromosome 21 are also associated with specific genetic/developmental disorders, and single gene defects in specific genes on chromosome 21 can lead to mental retardation or other defects. An excellent example is autosomal recessive cystathionine beta synthase deficiency, which leads to profound mental retardation, vascular problems, and ocular problems. Since all the deleterious aspects of Down syndrome are seen in the general population in individuals without detectable chromosome anomaly, understanding these problems in individuals with Down Syndrome promises to have a very wide overall health relevance. Over the past 10 years, a major focus of research on down syndrome has been the generation of chromosome 21 maps which serve as a framework to analyze which genes and regions of the chromosome are involved in which aspects of Down syndrome and other chromosome 21 defects. This Program Project played a major role in the development of these maps, and in the characterization of a small number of genes associated with, or likely to be associated with, chromosome 21 diseases. The Program Project has evolved to the point where its goals are much more directly oriented to specific aspects of the phenotype of Down Syndrome and how these arise. Investigations are now proposed to take advantage of the physical map, the phenotype map, and unique animal models related to Down Syndrome to specifically isolate and characterize the functions in mammalian development of genes responsible for aspects of Down Syndrome including mental retardation (Korenberg, Kraus, Patterson, Gardiner), immune deficits (Jones), leukemia (Drabkin), heart disease (Korenberg, Gardiner), and in the isolation of new genes from chromosome 21 which may play a role in these diseases (Kao, Korenberg, Gardiner). The proposed studies take advantage of a virtually unique set of patient derived cell lines and of transgenic and aneuploid mouse technologies as well as modern molecular methods and reagents such as Yeast Artificial Chromosomes and fluorescence in situ hybridization technologies. We anticipate that this evolution of the Program Project will result in new, clinically significant information at an increasing pace over the next 5 years which will have a significant impact on our understanding of human health and development and of the various pathologies associated with Down Syndrome.
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