FREQUENCY OF EXON-15 MISSENSE MUTATION (442D-G) IN CHOLESTERYL ESTER TRANSFER PROTEIN GENE IN HYPERALPHALIPOPROTEINEMIC JAPANESE SUBJECTS

Cholesteryl eater transfer protein (CETP) transfers cholesteryl ester from high density lipoprotein (HDL) to apo B-containing lipoproteins. The hyperalphalipoproteinemia caused by CETP deficiency is fairly comm on in Japan and one of the most common mutations in the CETP gene is t he splicing defect of the intron 14, the allelic frequency of which ha s been shown to be 0.0049 in the Japanese general population. Recently , we have reported a missense mutation in exon 15 of the CETP gene (44 2D:G), showing a dominant effect on the CETP activity and HDL-choleste rol level. In the current study, we determined the frequency of this n ew mutation in Japanese hyperalphalipoproteinemic (HDL-cholesterol gre ater than or equal to 100 mg/dl) subjects. A rapid and easy screening method for this new mutation was developed using a polymerase chain re action (PCR)-mediated site-directed mutagenesis. Among 117 Japanese hy peralphalipoproteinemic subjects (HDL-cholesterol; 116.7 +/- 16.5 mg/d l, mean +/- S.D.) without the intron 14 splice defect, three homozygot es (2.5%) and 34 heterozygotes (29.1%) were found to have the 442D:G m utation. The relative allelic frequency of this mutation was calculate d to be 0.17. One of the homozygotes for the 442D:G mutation was the p atient previously described by us as having hyperalphalipoproteinemia with corneal opacity and coronary heart disease. This was the first re ported subject homozygous for the CETP deficiency who also demonstrate d atherosclerotic symptoms. In homozygous subjects, CETP activity rang ed from 37% to 62% of the normal value, which was consistent with the results obtained from the transient expression experiment previously r eported; however, the specific activity of CETP was not as low as expe cted. These results demonstrate that this 442D:G mutation is as common as the intron 14 splice defect in Japanese hyperalphalipoproteinemic subjects and that CETP deficiency may not always be an anti-atheroscle rotic state.