Apolipoproteins are lipid binding proteins involved in the transport of cholesterol, triglycerides and phospholipids in the plasma. Defects in the structure or biosynthesis of these proteins may result in disorders of the plasma lipid transport system and the development of premature coronary artery disease. We have recently shown that the genes coding for three apolipoproteins - namely, AI (apoAI), CIII (apoCIII) and AIV (apoAIV) - are clustered within a 15 kilobase DNA segment on the long arm of human chromosome 11. We have also shown that the haplotypes of eleven restriction site polymorphisms located within and near this gene cluster comprise a highly informative marker for genetic and epidemiological studies. A long term comprehensive characterization of possible mutations in the apoAI, apoCIII and apoAIV genes resulting in dyslipoproteinemias and the development of premature coronary artery disease, requires both the identification of specific haplotypes cosegregating and associated with these disorders, and the availability of gene expression systems in which the function of the genes represented by these haplotypes can be evaluated. We therefore propose to use the polymorphisms in this apolipoprotein gene cluster for genetic linkage between segregating haplotypes and familial high density lipoprotein deficiency (hypoalphalipoproteinemia), and for association of specific haplotypes with premature coronary artery disease and hypoalphalipoproteinemia. In parallel, we will continue with the development of gene expression systems in which the specific transcription, pre-mRNA splicing, translation and regulation of expression by cis- and trans-acting factors of all three cloned apoAI, apoCIII, and apoAIV genes, can be evaluated. We will use these expression systems for the study of apoAI, apoCIII and apoAIV genes representing specific haplotypes that co-segregate with hypoalphalipoproteinemia and haplotypes associated with premature coronary artery disease and hypoalphalipoproteinemia. Discovery and detailed structural and functional characterization of mutations within or near the apoAI, apoCIII, and apoAIV genes resulting in hypoalphalipoproteinemia and premature coronary artery disease, will facilitate both further understanding of mechanisms by which the function of a gene may be impaired and the development of genetic tests by which early diagnosis and treatment of these disorders may be accomplished.
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