Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Ohtani, Rumiko; Inazu, Akihiro; Noji, Yoshihiro; Wakasugi, Takanobu; Miwa, Kenji; Tada, Hayato; Kawashiri, Masa‐aki; Noguchi, Tohru; Nohara, Atsushi; Kobayashi, Junji; Koizumi, Junji; Yamagishi, Masakazu; Mabuchi, Hiroshi

doi:10.1016/j.cca.2011.11.010

Cited by 12 publications

(5 citation statements)

References 43 publications

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“…Furthermore, it is likely to truncate the monomers, impairing the synthetase-binding domain. Similar variants leading to protein truncation have been reported previously [13, 19, 20]. Therefore, we believe that the variant c.773 + 4A > C is associated with the pathogenesis of CTLN1.…”

Section: Discussionsupporting

confidence: 85%

Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review

Lin¹,

Gao

Lü

et al. 2019

BMC Med Genet

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Background Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder of the urea cycle caused by a deficiency in the argininosuccinate synthetase (ASS1) enzyme due to mutations in the ASS1 gene. Only a few Chinese patients with CTLN1 have been reported, and ASS1 gene mutations have been identified sporadically in China. Case presentation A Chinese family with one member affected with mild CTLN1 was enrolled. Targeted exome sequencing was performed on the proband, and Sanger sequencing was used to validate the detected mutation. We also reviewed the genetic and clinical characteristics of CTLN1 in Chinese patients that have been published to date. Newborn screening showed remarkably increased concentrations of citrulline with elevated ratios of citrulline/arginine and citrulline/phenylalanine, and the patient presented with a speech delay at age three. The urinary organic acid profiles were normal. A novel homozygous splicing variant c.773 + 4A > C in the ASS1 gene was identified in the proband, and it was predicted to affect splicing by in silico analysis. To date, only nine Chinese patients with CTLN1 have been reported, with a total of 15 ASS1 mutations identified and no high frequency or hot spot mutations found; the mutation spectrum of Chinese patients with CTLN1 was heterogeneous. Conclusions We described a mild Chinese CTLN1 case with a novel homozygous splicing variant c.773 + 4A > C and reviewed previous genotypes and phenotypes in Chinese patients with CTLN1. Thus, our findings contribute to understanding the molecular genetic background and clinical phenotype of CTLN1 in this population. Electronic supplementary material The online version of this article (10.1186/s12881-019-0836-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review

Lin¹,

Gao

Lü

et al. 2019

BMC Med Genet

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“…Unfortunately, the causes of the extremely high HDL-C in subjects in this study are unclear because gene sequencing and measurement of CETP activity were not conducted. However, it has been reported that in half of individuals with high HDL-C in Japan a CETP gene mutation is responsible [43].…”

Section: Discussionmentioning

confidence: 99%

High Incidence of Diabetes in People with Extremely High High-Density Lipoprotein Cholesterol: Results of the Kanagawa Investigation of Total Checkup Data from the National Database-1 (KITCHEN-1)

Nakajima

Higuchi

Iwane

et al. 2019

JCM

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Background: It is unknown whether extremely high high-density lipoprotein cholesterol (HDL-C) has a protective effect against diabetes, which plays a key role in cardiovascular disease. Methods: In a community-based cohort study of 387,642 subjects (40–68 years old) without diabetes, the incidence of diabetes 6 years later was determined according to baseline HDL-C (≤39, 40–49, 50–59, 60–69, 70–79, 80–89, 90–99, 100–109, or ≥110 mg/dL). Results: At baseline, HDL-C ≥100 mg/dL was present in 12,908 subjects (3.3%), who had a better lipid profile and a high prevalence of heavy alcohol consumption and habitual exercise. The incidences of diabetes according to baseline HDL-C were 14.7, 11.2, 7.7, 5.3, 3.8, 2.8, 2.7, 2.5, and 3.5 per 1000 person-years, respectively. The adjusted relative risks (ARRs) for diabetes showed concave relationships with HDL-C, with minima at 80–89 mg/dL. The ARR (95% CI) of the lowest HDL-C category was 1.56 (1.40–1.74) and of the highest HDL-C category was 1.46 (1.18–1.81) (both p < 0.001), regardless of alcohol consumption. The latter ARR was higher in men (n = 219,047) (2.45 (1.70–3.53), p < 0.0001) after adjustment for baseline glycemic index. Conclusion: Both extremely high and low HDL-C represent risks for diabetes, which deserves further study.

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“…p.Leu168 is not evolutionarily conserved (S4 Fig), but introducing a proline at this position could make the backbone less flexible and affect protein folding. Ohtani et al [23] have found that L278R is not secreted. p.Leu278 is highly conserved and contributes to the lining of the hydrophobic tunnel.…”

Section: Plos Onementioning

confidence: 99%

Variants in the CETP gene affect levels of HDL cholesterol by reducing the amount, and not the specific lipid transfer activity, of secreted CETP

Ølnes,

Teigen,

Laerdahl

et al. 2023

PLoS ONE

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Background Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia. Methods HEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay. Results Four of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, p<0.001). Thus, the secreted variants had similar specific lipid transfer activities. Conclusion The effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants.

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Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects

Cited by 12 publications

References 43 publications

Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review

Citrullinemia type I is associated with a novel splicing variant, c.773 + 4A > C, in ASS1: a case report and literature review

High Incidence of Diabetes in People with Extremely High High-Density Lipoprotein Cholesterol: Results of the Kanagawa Investigation of Total Checkup Data from the National Database-1 (KITCHEN-1)

Variants in the CETP gene affect levels of HDL cholesterol by reducing the amount, and not the specific lipid transfer activity, of secreted CETP

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