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Updated: May 27, 2026
Isolation and Analysis of Plasma Lipoproteins by Ultracentrifugation
Published on: January 28, 2021
Novel mutations of cholesteryl ester transfer protein (CETP) gene in Japanese hyperalphalipoproteinemic subjects
Rumiko Ohtani1, Akihiro Inazu, Yoshihiro Noji
1Department of Laboratory Sciences, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kodatsuno, Japan.
Insights
Three new CETP gene mutations cause hyperalphalipoproteinemia (HALP) in Japan. These rare mutations, alone or with common ones, lead to varying HALP severity, highlighting genetic diversity in lipid disorders.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease
Background:
- Hyperalphalipoproteinemia (HALP) in Japan is often linked to CETP gene mutations.
- Two common mutations (D442G and Intron 14 splicing donor site +1G>A) are known, but rare mutations also exist in Japanese HALP subjects.
Purpose of the Study:
- To identify and characterize novel CETP gene mutations responsible for HALP in Japanese individuals.
- To investigate the functional impact of identified mutations on CETP protein function and splicing.
Main Methods:
- Genomic DNA analysis using restriction fragment length polymorphism (RFLP) and sequencing.
- Functional studies involving CETP minigene constructs and cDNA expression vectors in COS-1 cells to assess splicing and secretion defects.
Main Results:
- Identified three novel CETP gene mutations in HALP subjects: a compound heterozygote (c.653_654delGGinsAAAC/Intron 14 +1G>A), a heterozygote (c.658G>A), and a homozygote (L261R).
- Confirmed that the c.658G>A mutation causes splicing abnormalities.
- Demonstrated that the L261R mutation impairs CETP protein secretion.
Conclusions:
- Three novel CETP gene mutations are identified as causes of HALP due to CETP deficiency.
- The findings suggest that multiple rare CETP mutations, individually or in combination with prevalent mutations, contribute to the spectrum of HALP severity in the Japanese population.
Background:
The half of hyperalphalipoproteinemia (HALP) in Japan is caused by CETP gene mutations. Other than two prevalent mutations (D442G and Intron 14 splicing donor site +1G>A), some rare CETP mutations are found in Japanese HALP subjects.
Methods:
CETP gene analysis of genomic DNA from subjects was performed by restriction fragment length polymorphism (RFLP) and sequencing analysis. Mutations which were suspected to cause a splicing defect or a protein secretion defect were investigated in COS-1 cells transfected with a CETP minigene construct or a cDNA expression vector.
Results:
Each of three subjects was identified as a carrier of CETP gene mutation of a compound heterozygote of c.653_654delGGinsAAAC and Intron 14 splicing donor site +1G>A, a heterozygote of c.658G>A or a homozygote of L261R. The c.658G>A mutation was located at the last nucleotide of exon 7, and it was confirmed to cause splicing abnormality revealed by the CETP minigene analysis. The L261R CETP was not secreted to conditioned media of the cells.
Conclusions:
Three novel CETP gene mutations are responsible for HALP by CETP deficiency. It is predicted that there are more rare CETP gene mutations in Japanese, and these multiple rare mutations alone or a combination with each of prevalent mutations is responsible for mild-to-moderate or marked HALP, respectively.
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