This study aimed at investigating the molecular basis of Down's syndrome (DS). This syndrome, first described more than a century ago, is still the most common genetic abnormality, occurring once every 600-800 live births. It is a unique genetic disorder which results from the presence in the cell of an extra copy of chromosome 21, or a portion of it, the 21q22 segment. DS patients suffer from various morphological defects, they are mentally retarded and those who survive past their mid-30s usually develop Alzheimer's disease. The risk of a child being born with trisomy 21 increases sharply with maternal age; since there is presently a trend for many couple to postpone parenthood until the fourth decade of life, the incidence of DS babies is expected to increase. Moreover, because of continuous improvement in all aspects of clinical treatment, life expectancy of DS patients has tripled over the last two decades. Thus, despite the institution of prenatal screening by amniocentesis, the prevalence of DS individuals in our society will not significantly decrease in the near future. The long-term objective of this research is to elucidate at the molecular level how extra copy of normal chromosome 21 genes produce the DS phenotype. The ultimate goal is to isolate those genes and determine how increased amounts of their gene products lead to specific defects found in the syndrome. One set of experiments will further assess the biochemical mechanism by which elevated CuZnSOD generates phenotypic effects in DS. This will entail the analyses of transgenic mice with elevated CuZnSOD and low catalase and correlating the severity of the symptoms to that of parental transgenic-CuZnSOD mice. In parallel the CuZnSOD induced abnormalities in neurotransmitter uptake and neuromuscular-junction structure will be studied in primary brain cultures of transgenic-CuZnSOD mice as well as in mouse embryonic stem cells transfected with CuZnSOD expression vector. The relevance of the liver type phosphofructokinase (PFKL) gene to DS will be further explored by constructing transgenic mice overexpressing PFKL and analyzing these mice for morphologic changes. The interrelations between three overexpressed DS genes: CuZnSOD, PFKL and S100 beta will be explored by producing transgenic animals harboring different combinations of these genes. This should lead to a better understanding of how an imbalance expression of these genes contribute to the DS phenotype. Finally cDNAs corresponding to the chromosome 21 encoded zinc finger genes ZF21-1 and ZF21-2 will be isolated, characterized and the possible role of their gene products in transactivation of other genes studied. The information gained in this study should permit definition of the biochemical pathways affected in the syndrome, and hopefully allow the development of therapies to ameliorate or prevent at least some of the more serious symptoms of DS and related disorders.
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