Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Reference Assembly: GRCh37/hg19
Position: Chr19:45412278 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs267606663
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a patient with an abnormal blood lipid profile and lipid deposits (xanthomas) throughout her body, but it was considered unlikely to be the primary cause of the condition (Moriyama et al., 1996). The carrier was a 54-year-old Japanese woman with elevated levels of cholesterol and triglycerides in blood and xanthomas under the skin of her palms, in her bones, and in the back surface of her eyes. Moreover, a bone marrow biopsy revealed lipid-laden “foam” macrophages, typically found in fatty deposits on blood vessel walls. Isoelectric focusing showed two ApoE species: one migrating to the position of the common ApoE3 isoform and the other to the position of R176C (ApoE2). DNA sequencing revealed the ApoE2-migrating species was in fact an ApoE3 allele with an R242Q substitution resulting in an additional negative charge. Based on its migration pattern and the city where the patient was identified, the variant was named ApoE2 Fukuoka.

This variant was absent from the gnomAD variant database (v2.1.1, June 2022).

Biological Effect

The binding of the mutant protein to the surface of human skin fibroblasts was similar to that of wildtype ApoE3 as revealed by an assay using recombinant R242Q produced in COS-1 cells. The two proteins’ affinities for heparin were also similar. Based on these findings, the authors hypothesized the mutation was not the primary cause of the patient’s condition. However, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 20.9, slightly above the threshold of 20 used to predict deleterious effects (CADD v.1.6, June 2022).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y, Arakawa K. Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta. 1996 Jun 11;1301(3):185-90. PubMed.

Further Reading

No Available Further Reading