A new mutation in the human cetp gene: The first caucasian north american subject

Plasma Cholesteryl Ester Transfer Protein (CETP) contains 476 residues & catalyzes the heteroexchange of cholesteryl esters & triglycérides between plasma High Density Lipoproteins & Very Low & Low Density Lipoproteins & us such is an essential component of the Reverse Cholestoiol Transport System. CETP deficiency, although rare, predominates in the .Japanese population & is associated with high plasma HDL levels & longevity. A 57 year old Caucasian female resident of Nova Scotia presented with elevated total plasma cholesterol i 10 mmol/I), HDL-C (5.7 mmol/1) & Apo A-I (272 mg/dl). Her Apo B levels were slightly elevated (127 mg/dl) as was hf LDL cholesterol (3.6 mmot/1) & plasma triglycérides (1.4 mmol/I). Density gradient ultracentrifugation of her plasma demonstrated the preponderance of large HDL, particles. Incubation of the subject's plasma revealed a complete absence of cholesteryl ester transfer activity consistent with very low proportions of this lipid in her VLDL. Monoclonal antibodies directed against the C-terminus of human CETP failed to detect the presence of this epkope in undiluted plasma. Molecular analysis of lymphocyte DNA by PCR using specific primers for each of the 16 exons & exon/intron junctions of the CETP gene followed by cloning & sequencing showed the presence of a single nucleotide substitution (CGATGA) at position 836 resulting in the conversion of 268Argr>Stop in both alleles. No additional mutation was observed in the entire coding sequence or intron/exon junctions. The lack of CETP activity associated with a truncation of the CETP protein at residue 268 confirms the importance of the C-terminal domain in activity & is the first report of this mutation. Our subject is also the first Caucasian North American with CETP deficiency. Supported by MRC Canada.