Genetics
Two newly discovered CETP mutations block protein secretion, explaining more than 60 percent of severe high-HDL cases in Japan (J Lipid Res 2002)
Original title: Two novel missense mutations in the CETP gene in Japanese hyperalphalipoproteinemic subjects: high-throughput assay by Invader assay
Since CETP deficiency is a common cause of hyperalphalipoproteinemia (HALP) in Japan, this study screened 196 subjects with marked HALP (HDL-cholesterol 100 mg/dL or higher) and identified two novel missense mutations in the CETP gene, L151P and R282C, found in subjects who were compound heterozygous with the known D442G mutation and had significantly lower plasma CETP than D442G heterozygotes alone. In COS-7 cells expressing wild-type or mutant CETP, the two mutants showed markedly reduced protein secretion into the media (0% and 39% of wild-type for L151P and R282C respectively). Using the Invader assay to screen seven mutations including these two novel ones across 466 unrelated HALP subjects (HDL-cholesterol 80 mg/dL or higher), the novel mutations were rare, though L151P recurred in unrelated marked-HALP subjects. CETP deficiency was found to contribute to 61.7% of marked HALP and 31.4% of moderate HALP cases in the Japanese population.
Original abstract
Cholesteryl ester transfer protein (CETP) deficiency is one of the most important and common causes of hyperalphalipoproteinemia (HALP) in the Japanese. CETP deficiency is thought to be a state of impaired reverse cholesterol transport, which may possibly lead to the development of atherosclerotic cardiovascular disease despite high HDL-cholesterol (HDL-C) levels. Thus, it is important to investigate whether HALP is caused by CETP deficiency. In the present study, we identified two novel missense mutations in the CETP gene among 196 subjects with a marked HALP (HDL-C > or = 2.59 mmol/l = 100 mg/dl). The two missense mutations, L151P (CTC-->CCC in exon 5) and R282C (CGC-->TGC in exon 9), were found in compound heterozygous subjects with D442G mutation, whose plasma CETP levels were significantly lower when compared with those in D442G heterozygous subjects. In COS-7 cells expressing the wild type and mutant CETP, these two mutant CETP showed a marked reduction in the secretion of CETP protein into media (0% and 39% of wild type for L151P and R282C, respectively). These results suggested that two novel missense mutations cause the decreased secretion of CETP protein into circulation leading to HALP. By using the Invader assay for seven mutations, including two novel mutations of the CETP gene, we investigated their frequency among 466 unrelated subjects with HALP (HDL-C > or = 2.07 mmol/l = 80 mg/dl). Two novel mutations were rare, but L151P mutation was found in unrelated subjects with a marked HALP. Furthermore, we demonstrated that CETP deficiency contributes to 61.7% and 31.4% of marked HALP and moderate HALP in the Japanese, respectively.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.