[New approach to pathogenesis of genetic hyperlipoproteinemias].

Genetic hyperlipoproteinemias are produced by defects or abnormalities of several enzymes, apolipoproteins and transfer proteins relating to lipoprotein metabolism. Abnormalities of the LDL receptor cause familial hypercholesterolemia (FH) and the deficiency of cholesteryl-ester transfer protein (CETP) causes familial hyperalphalipoproteinemia. Here, abnormalities of the LDL-receptor genes and CETP gene are described. More than 70 mutants of LDL-receptor gene have been reported, and we discovered 4 mutants in the Hokuriku district of Japan. Compared with FH-Tonami-1, FH-Tonami-2 showing a partial defect of the LDL-binding domain of the receptor, is a genetically determined mild type of FH. Only 10% of the LDL receptor abnormalities in FH have been clarified, and the causes of the remaining 90% are unknown at present. CETP catalyzes the transfer of cholesteryl ester from HDL to other lipoproteins. We found a familial hyperalphalipoproteinemia produced by the CETP deficiency. A point mutation in the splice donor site of intron 14 in the CETP gene was found in all Japanese patients with CETP deficiency. CETP deficiency produces an antiatherogenic lipoprotein profile in high HDL-cholesterol level and low IDL- and LDL-cholesterol levels. We developed a rapid screening method for the splicing defect of CETP gene, by means of primer-specific restriction map modification. The frequency of the mutated allele in the general population was estimated to be 0.81%, and the mutant was frequent in Japanese subjects with hyperalphalipoproteinemia. In summary, the detection of gene abnormalities is essential for understanding lipoprotein abnormalities and clinical manifestations in genetic hyperlipoproteinemias.