Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45411893 ->G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Frame Shift
Codon Change: GAG to GAA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant, a nucleotide insertion causing a frameshift, was found in a Dutch family in which some carriers suffered from hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, a condition characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease (Dijck-Brouwer et al., 2005). The proband developed lipid deposits under his skin starting at age 18, had elevated cholesterol levels at age 35 and was found to have an HLPP3-like lipid and lipoprotein profile at age 49. Due to a genotyping artifact, he was first thought to be homozygous for the R176C (APOE2) allele, a common cause of HLPP3. However, further analyses revealed he was an APOE2/3 heterozygote carrying the E114Gfs mutation on an APOE3 background. The mutation was named APOE3 Groningen, in honor of the city in which it was discovered.

Subsequent genotyping of 19 family members identified five mutation carriers, spanning three generations. Only three carriers were affected, however, having elevated levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) in serum. Interestingly, all three of these individuals, including the proband, were APOE2 heterozygotes, while the two unaffected carriers were homozygous for the more common APOE3 allele.

The authors concluded that E114fs alone, in heterozygote form, is probably insufficient to cause disease. Of note, heterozygote carriers of other mutations also coding for truncated ApoE species, W38Ter, R154fs, and W5Ter, have been reported to suffer from HLPP3 when carrying an APOE2 allele. Moreover, other genetic or environmental factors may contribute to disease. Indeed, five of the mutation non-carriers in the Dutch family, three APOE3 homozygotes and two APOE2/3 heterozygotes, had elevated lipid indices.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, Apr2022).

Biological Effect

This variant results from the insertion of a guanine in codon 113 or 114 causing a frameshift that results in the replacement of E114 by a glycine and the generation of a premature stop codon at position 164 (Dijck-Brouwer et al., 2005). The predicted consequence is either the expression of a truncated protein and/or the elimination of ApoE synthesis caused by nonsense-mediated RNA decay. Its biological effect is unknown, but together with ApoE2, which binds very poorly to low-density lipoprotein receptors (LDLRs), it is expected to substantially reduce ApoE functionality.

How much a loss or reduction of ApoE function might affect or contribute to the pathology of AD has been an important question in the field (see e.g. Belloy et al., 2019). The cognitive health of several aged, heterozygous carriers of other loss-of-function (LoF) variants suggests a 50 percent reduction is benign and perhaps protective when in phase with APOE4 (Chemparathy et al., 2024; Vance et al., 2024). Data from mouse models are mixed. In general, reducing or eliminating ApoE in mouse models of amyloid deposition appears to reduce amyloid accumulation, but selectively reducing ApoE in astrocytes, microglia, neurons, or brain endothelial cells suggests cell type-specific effects that can be beneficial, neutral, or harmful (for more information, see APOE Loss of Function Variants).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE W38Ter
3. APOE W5Ter

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Dijck-Brouwer DA, van Doormaal JJ, Kema IP, Brugman AM, Kingma AW, Muskiet FA. Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem. 2005 Jul;42(Pt 4):264-8. PubMed.
2. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
3. Chemparathy A, Le Guen Y, Chen S, Lee EG, Leong L, Gorzynski JE, Jensen TD, Ferrasse A, Xu G, Xiang H, Belloy ME, Kasireddy N, Peña-Tauber A, Williams K, Stewart I, Talozzi L, Wingo TS, Lah JJ, Jayadev S, Hales CM, Peskind E, Child DD, Roeber S, Keene CD, Cong L, Ashley EA, Yu CE, Greicius MD. APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron. 2024 Apr 3;112(7):1110-1116.e5. Epub 2024 Jan 31 PubMed.
4. Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.

Other Citations

1. R154fs

Further Reading

No Available Further Reading