MOLECULAR-GENETIC STUDY OF FAMILIAR HYPERLIPOPROTEINEMIA RELATED TO ATHEROSCLEROSIS

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The purpose of this study is to elucidate the mechanism of hyperlipoproteinemia on the basis of molecular biology and genetics and contribute to the prevention of atherosclerotic vascular diseases.1) Analysis of the LDL-receptor gene mutation in familial hypercholesterolemia (FH) : A point mutation at the splice donor site of intron 12 was identified in 7 out of 24 FH homozygotes from independent families. This mutation was detected in 15% of the patients with heterozygous FH as the most popular mutation of LDL receptor gene among Japanese. All the three mutations with a large deletion in LDL receptor gene were found to be resulted from Alu-Alu recombination.2) Changes in apolipoproteins as a cause of or related to hypercholesterolemia : (a) We detected a case of moderate hyperlipidemia, whose LDL showed a decrease in affinity to the cell surface receptor (s). The replacement of amino acid 3500 in apolipoprotein B (apo B), which is a relatively common mutation related to hypercholester … More olemia in Europe, was not found in this mutant.The analysis of apo B gene is now under investigation.(b) In WHHL rabbit, an animal model of FH,there were marked decreases in apo A-I and A-IV,making a sharp contrast to the alimentary hyperlipedemia, in which both apo A-I and A-IV were in the nomal range. The decrease in these apolipoproteins could be an additional factor leading to the progression of atherosclerosis through the disturbance of reverse cholesterol transport.3) Deficiency in lipoprotein lipase (LPL) and hepatic lipase (HL) as a cause of hypertriglyceridemia : LPL deficiency in heterozygous state was frequently found in type IV hyperlipoproteinemia. High alcohol intake and hyperinsulinemia or glucose intolerance were the factors, which manifest hypertriglyceridema in patients with LPL deficiency. The complete deficiency in HL is rare. We found a case of this kind of disorder and identified the site of mutation in exon 2 (T*G). Peculiar characteristic on HL deficiency was the presence of TG-rich LDL together with TG-rich HDL. Less