Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45411119 G>-
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Frame Shift
Codon Change: GGT to GTC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This mutation, which appears to eliminate ApoE expression, was identified in heterozygous form in a German man and two family members, all of whom also carried the APOE G145D variant, and suffered from severe hyperlipoproteinemia type III (HLPP3) (Feussner et al., 1992). The condition, also known as familial dysbetalipoproteinemia, is characterized by the accumulation of remnants of triglyceride-rich lipoproteins and early onset atherosclerosis and heart disease. All carriers had an increased ratio of very low-density lipoprotein (VLDL) cholesterol to triglycerides in plasma characteristic of HLPP3.

Because this mutation was present together with G145D, a variant described as dominant with variable penetrance for HLPP3, its phenotypic effects are difficult to assess. Given that the authors were unable to detect the G49Vfs truncated protein in plasma, they speculated the mutation contributes to HLPP3 risk by reducing ApoE levels. Consistent with this proposal, other patients with ApoE deficiency have been diagnosed with HLPP3 (e.g., A227_E230del, W228Ter, E98Nfs, R154Afs; Mabuchi et al., 1989; Kurosaka et al., 1991).

Of note, a study describing several heterozygotes carrying other variants that eliminate APOE expression suggests partial loss of ApoE is tolerated, with carriers remaining cognitively healthy beyond age 75 (Chemparathy et al., 2024, see APOE W5Ter).  Moreover, when these loss-of-function variants were present on the same chromosome as the major AD risk variant C130R (APOE4), they appeared to decrease AD risk.

G49Vfs was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Biological effect

This mutation is a deletion of one of three consecutive guanines found in codons L48 (CTG) and G49 (GGT), causing a frameshift predicted to create a premature stop codon at position 78 (Feussner et al., 1992). Several biochemical methods, including isoelectric focusing, SDS polyacrylamide-gel electrophoresis, two-dimensional gel electrophoresis, and immunoblotting, failed to detect the predicted truncated species, suggesting the encoding mRNA undergoes nonsense-mediated decay.

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). As noted above, the cognitive health of several aged, heterozygous carriers of other loss-of-function variant 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 G145D
2. APOE A227_E230del
3. APOE W228Ter
4. APOE W5Ter
5. APOE C130R (ApoE4)

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Feussner G, Funke H, Weng W, Assmann G, Lackner KJ, Ziegler R. Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/'null' genotype. Eur J Clin Invest. 1992 Sep;22(9):599-608. PubMed.
2. Mabuchi H, Itoh H, Takeda M, Kajinami K, Wakasugi T, Koizumi J, Takeda R, Asagami C. A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism. 1989 Feb;38(2):115-9. PubMed.
3. Kurosaka D, Teramoto T, Matsushima T, Yokoyama T, Yamada A, Aikawa T, Miyamoto Y, Kurokawa K. Apolipoprotein E deficiency with a depressed mRNA of normal size. Atherosclerosis. 1991 May;88(1):15-20. PubMed.
4. 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.
5. 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.
6. 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. E98Nfs

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading