Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45412014 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been reported in several individuals with abnormal blood lipid profiles. It was first identified in a Canadian family with a mildly abnormal lipoprotein phenotype and a history of early coronary artery disease (Minnich et al., 1995). Nine heterozygous carriers in the family had levels of very low-density lipoprotein (VLDL) cholesterol and triglycerides roughly two-fold higher than those of nine non-carriers in the same family. 

The variant was also found in a 63-year-old Thai woman living in the Netherlands and two of her three children (Koopal et al., 2017). They had a family history of cardiovascular disease and the woman had a blood lipid and lipoprotein profile typical of hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia. HLPP3 is characterized by the accumulation of remnants of triglyceride-rich lipoproteins and early onset atherosclerosis and heart disease. Both children had profiles consistent with early stage HLPP3. The proband also had a history of autoimmune hyperthyroidism and Behcet’s disease, a rare disorder that causes blood vessel inflammation, in this case affecting the retina.

A subsequent study reported the variant in a 47-year-old Chinese man with elevated low-density lipoprotein (LDL) cholesterol (Wang et al., 2020). He had no family history of cardiovascular disease.

Thus, the effect of this variant, at least in heterozygotes, appears to be relatively mild. None of the carriers described to date have had xanthomas, lipid deposits under the skin often found in patients with HLPP3 or related conditions.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Biological Effect

An analysis of the levels of ApoE in VLDL particles isolated from members of the Canadian family revealed an enrichment of the mutant protein compared with ApoE3 or ApoE4 (Minnich et al., 1995). To test if this was due to a deficiency in clearance, the authors isolated R154H ApoE from a carrier, complexed it with the artificial lipid DMPC, and measured its ability to displace labeled LDL from the surface of cultured fibroblasts. Binding was approximately 80 percent of wildtype ApoE3.

The mutant protein also displayed reduced affinity for heparin, as assessed by heparin-Sepharose chromatography (Minnich et al., 1995). The latter finding is consistent with a model predicting R154 is one of eight amino acids lining a shallow groove that binds and makes direct contact with the sulfo groups of heparan sulfate proteoglycans (Libeu et al., 2001).

R154 is highly conserved in mammals (Frieden, 2015), and R154H’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022). Wang and colleagues classified the variant as likely pathogenic (Wang et al., 2020).

Of note, another variant at this same position, R154S (Christchurch), has been tied to protection against autosomal dominant Alzheimer's disease (AD) when in homozygous form, and paradoxically, also found in a family with AD lacking other neurodegenerative mutations. In addition, an artificial substitution at the site, R154A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 more strongly than to ApoE3 or ApoE2 and activates pro-inflammatory pathways (Zhou et al., 2023).

Nomenclature Notes

Because the isoelectric point of R154H is similar to that of the common APOE3 isoform (only slightly more acidic), Minnich and colleagues named the variant apoE3' (Arg136-->His), using the numbering of the mature 299 amino acid-long ApoE protein (Minnich et al., 1995).

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References

Paper Citations

1. Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M, Davignon J. Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3' (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res. 1995 Jan;36(1):57-66. PubMed.
2. Koopal C, Marais AD, Westerink J, Visseren FL. Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy. J Clin Lipidol. 2017 Jan - Feb;11(1):12-23.e1. Epub 2016 Oct 13 PubMed.
3. Wang H, Yang H, Liu Z, Cui K, Zhang Y, Zhang Y, Zhao K, Yin K, Li W, Zhou Z. Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. Epub 2020 Aug 6 PubMed.
4. Libeu CP, Lund-Katz S, Phillips MC, Wehrli S, Hernáiz MJ, Capila I, Linhardt RJ, Raffaï RL, Newhouse YM, Zhou F, Weisgraber KH. New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem. 2001 Oct 19;276(42):39138-44. Epub 2001 Aug 10 PubMed.
5. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.

Other Citations

1. R154S (Christchurch)

External Citations

1. Zhou et al., 2023

Further Reading

No Available Further Reading