Overview

Clinical Phenotype: Hyperlipoproteinemia Type III, Cardiovascular Disease, Kidney Disorder
Position: (GRCh38/hg38):Chr19:44908909 C>G
Position: (GRCh37/hg19):Chr19:45412166 C>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to GAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 55-year-old Japanese woman with hyperlipoproteinemia type III (HLPP3) (Okubo et al., 1998). The disorder, a.k.a. familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood. The proband also had coronary atherosclerosis and lipid deposits beneath the skin known as tuberoeruptive xanthomas, conditions often associated with HLPP3. Moreover, she also had diabetes mellitus (Okubo et al., 1998), and was later found to have kidney pathology known as diabetic nephrosclerosis (Hayakawa et al., 2002). Of note, Hayakawa and colleagues found no evidence of lipoprotein glomerulopathy, a rare kidney disorder associated with other APOE variants.

The variant was discovered when a discrepancy between the proband’s ApoE protein and genotype was identified (Okubo et al., 1998). Upon isoelectric focusing, the protein migrated as a single band to the position of the common R176C (APOE2) variant. However, genetic analysis revealed she was not homozygous for APOE2, but rather an APOE2/E3 heterozygote. Sequencing of exons 3 and 4 resolved the apparent inconsistency, revealing the APOE3 gene also had a Q205E substitution. The new variant was named APOE2 Toranomon based on its isoelectric migration and the Tokyo district where it was discovered.

The proband had no family history of atherosclerotic disease nor diabetes. Genotyping of her husband, two sons, daughter, and half-sister revealed one additional carrier: the proband’s daughter. At age 22, she remained healthy, without either HLPP3 or diabetes. Noting that hyperlipidemia is often observed in diabetics and that diabetes can aggravate HLPP3, the authors speculated diabetes could have contributed to the proband’s HLPP3. Also, the proband carried an APOE2 allele which, in homozygous form, is a common cause of HLPP3.

The variant was absent from 10 unrelated HLPP3 patients and 420 healthy controls (Okubo et al., 1998), as well as from the gnomAD variant database (v2.1.1, Sep 2022).

Biological Effect

The biological effect of this mutation is uncertain. The proband’s ApoE protein (composed of ApoE2 and the Q205E mutant) complexed with the artificial lipid DMPC competed poorly with labeled low-density lipoprotein (LDL) for binding to the surface of cultured human fibroblasts (Okubo et al., 1998). Its performance was roughly 25 percent of that of ApoE3. However, the proband’s ApoE competed similarly to ApoE isolated from APOE2/E3 heterozygotes. Since ApoE2 is known to have reduced affinity for LDL receptors, the findings suggest that most, if not all, of the proband’s defective binding can be attributed to the presence of ApoE2, rather than to the novel variant. In addition, heparin binding, as assessed by affinity chromatography, was similar to ApoE3 and ApoE2.

Of note, Q205 can be post-translationally modified which may modulate receptor binding (Uen et al., 2015). The addition of two methyl groups appears to decrease the positive electrical potential which may decrease receptor binding.

Although Q205 is evolutionarily conserved (Okubo et al., 1998), Q205E’s PHRED-scaled CADD score, which integrates diverse information in silico, was 13.6, falling short of the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. Okubo M, Aoyama Y, Harada K, Fukawa M, Tsukada T, Mokuno H, Yamada N, Murase T. A novel apolipoprotein E2 variant, E2Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis. Atherosclerosis. 1998 Sep;140(1):187-90. PubMed.
2. Uen YH, Liao CC, Lin JC, Pan YH, Liu YC, Chen YC, Chen WJ, Tai CC, Lee KW, Liu YR, Lin HT, Lin CY. Analysis of differentially expressed novel post-translational modifications of plasma apolipoprotein E in Taiwanese females with breast cancer. J Proteomics. 2015 Aug 3;126:252-62. Epub 2015 Jun 12 PubMed.

Other Citations

1. Hayakawa et al., 2002

Further Reading

No Available Further Reading