MOLECULAR GENETICS OF CHOLESTEROL TRANSPORT AND CHOLESTEROL REVERSE TRANSPORT DISORDERS

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LDL-RECEPTOR ABNORMALITIES IN FAMILIAL HYPERCHOLESTEROLEMIA.More than 150 different mutations in the LDL receptor gene have been reported in the world. We have collected 14 homozygotes and more than 1,300 heterozygotes of FH.Seven variants of LDL receptor gene have been identified in our laboratory. Four mutants showed large deletions detected by Southern blot analysis, and three mutants were point mutations detected by SSCP analysis and direct sequencing of PCR products. These seven mutants of 85 patients from 31 families accounted for only 15.5% of FH.FH Tonami-1 produces a mutant precursor of about 100 KDal which has no O-linked sugar domain. FH Tonami-2 has a variant of LDL receptor gene with 10Kb deletion eliminating exons 2 and 3. FH Tsuruga homozygote and FH Kanazawa-2 compound heterozygotes showed severe coronary heart disease. FH Morioka showed a point mutation from C to T in exon 9. Another compound heterozygote showed a new mutant named FH-Nanao.CHOLESTERYL-ESTER TRANSFER PR … More OTEIN (CETP) DEFICIENCY IN FAMILIAL HYPER-HDL-CHOLESTEROLEMIA.The genomic DNA of patients with CETP deficiency was used as a substrate for amplification of the CETP gene by PCR.At the 5' splice donor of intron 14 (position+1) there was a G to A change altering the strictly conserved G-T intron splice donor to A-T.We found two novel mutants of CETP gene. One splice donor site mutant is a thymidine insertion in +3 position in intron 14, which will, again, result in splicing defect. Another new mutant is a missense mutation in exon 15, producing change of aspartic acid into glycine. This mutant is also highly frequent, almost 1 in 10. Thus, these two common mutants produce at least 20 CEPT heterozygotes in 214 general subjects, and might raise the HDL-cholesterol levels and reduce coronary heart disease in the Japanese.DOUBLE HETEROZYGOTES OF FH AND CETP DEFICIENCY.We have screened CETP gene abnormalities in 348 FH patients, and found 16 double heterozygotes of LDL receptor gene and CETP gene, and 1 heterozygous FH patient combined with homozygous CETP deficiency. These double heterozygotes were often complicated by coronary heart disease, and 4 patients showed myocardial infarction and 4 showed angina pectoris. Thus, half of the 16 patients showed definite coronary heart disease. From these findings we suggest that atherogenicity of hyper-LDL-cholesterolemia in FH is more powerful than antiatherogenicity of hyper-HDL-cholesterolemia in CETP deficiency. Less