title: Two novel missense mutations in the CETP gene in Japanese hyperalphalipoproteinemic subjects: high-throughput assay by Invader assay.
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.
authors.affiliation: Research Department, R&D Center, BML, 1361-1 Matoba, Kawagoe, Saitama 350-1101, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagano
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ito
authors.forename: Takao
authors.initials: T
authors.lastname: Maruyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ishihara
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sagehashi
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Oka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kujiraoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hattori
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nakajima
authors.forename: Tohru
authors.initials: T
authors.lastname: Egashira
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kondo
authors.forename: Naohiko
authors.initials: N
authors.lastname: Sakai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D005838:Genotype; D006023:Glycoproteins; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*
chemical_list: C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins