A MISSENSE MUTATION IN THE CHOLESTERYL ESTER TRANSFER PROTEIN GENE WITH POSSIBLE DOMINANT EFFECTS ON PLASMA HIGH-DENSITY-LIPOPROTEINS

Plasma HDL are a negative risk factor for atherosclerosis. Cholesteryl ester transfer protein (CETP; 476 amino acids) transfers cholesteryl ester from HDL to other lipoproteins. Subjects with homozygous CETP de ficiency caused by a gene splicing defect have markedly elevated HDL; however, heterozygotes have only mild increases in HDL. We describe tw o probands with a CETP missense mutation (442 D:G). Although heterozyg ous, they have threefold increases in HDL concentration and markedly d ecreased plasma CETP mass and activity, suggesting that the mutation h as dominant effects on CETP and HDL in vivo. Cellular expression of mu tant cDNA results in secretion of only 30% of wild type CETP activity. Moreover, coexpression of wild type and mutant cDNAs leads to inhibit ion of wild type secretion and activity. The dominant effects of the C ETP missense mutation during cellular expression probably explains why the probands have markedly increased HDL in the heterozygous state, a nd suggests that the active molecular species of CETP may be multimeri c.