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Journal of Lipid Research, Vol. 43, 1011-1018, July 2002
Copyright © 2002 by Lipid Research, Inc.

Two novel missense mutations in the CETP gene in Japanese hyperalphalipoproteinemic subjects

Makoto Nagano^*,, Shizuya Yamashita^1,, Ken-ichi Hirano, Mayumi Ito^*, Takao Maruyama, Mitsuaki Ishihara^*, Yukiko Sagehashi^*, Tomoichiro Oka^*, Takeshi Kujiraoka^*, Hiroaki Hattori^*, Norimichi Nakajima, Tohru Egashira^*, Masatoshi Kondo^*, Naohiko Sakai and Yuji Matsuzawa

^* Research Department, R&D Center, BML, 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Nakajima Clinic, 17-1 Asahi-cho, Omagari, Akita 014-0013, Japan

¹ To whom correspondence should be addressed. e-mail: shizu{at}imed2.med.osaka-u.ac.jp

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 2.59 mmol/l = 100 mg/dl). The two missense mutations, L151P (CTCCCC in exon 5) and R282C (CGCTGC 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 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.

Abbreviations: BPI, bactericidal permeability increasing protein; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FRET, fluorescent resonance energy transfer; HALP, hyperalphalipoproteinemia; MAb, monoclonal antibodies; RCT, reverse cholesterol transport

Supplementary key words cholesteryl ester transfer protein deficiency • HDL-cholesterol • genotyping

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