Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Cardiovascular Disease, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908976_44908985 CCTGGGGCGA>-
Position: (GRCh37/hg19):Chr19:45412233_45412242 CCTGGGGCGA>-
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: GCC to -, TGG to -, GGC to -, GAG to -
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

In homozygous form, this deletion results in nearly complete elimination of ApoE protein (Feussner et al., 1996; Feussner 1996). Note that neurological data for this variant are unavailable. However, neurological phenotypes associated with other mutations resulting in complete ApoE loss (E98Nfs) or partial ApoE loss (e.g., W5Ter) have been described.

A227_E230del was first identified in homozygous form in a 30-year-old German man of Hungarian ancestry with ApoE deficiency and severe hyperlipoproteinemia type III (HLPP3). This condition, also known as familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease. The proband had only trace amounts of ApoE in plasma and, as expected, the protein was truncated. He also had multiple lipid deposits under the skin known as xanthomas. Microscopic examination of these deposits in the ear revealed lipid-laden macrophages, foam cells, which congregate in early atherosclerotic lesions.

Genetic analysis of 24 of the proband’s relatives revealed 10 heterozygotes with elevated levels of triglycerides and very low-density lipoprotein (VLDL) cholesterol, and a high ratio of VLDL cholesterol to triglycerides, indicating delayed catabolism of lipoprotein remnants that can cause atherosclerosis. Consistent with these findings, other patients with ApoE deficiency have been diagnosed with HLPP3, with similar alterations of their blood lipid and lipoprotein profiles (see e.g., E98Nfs, c.237-1A>G and W228Ter; also, Mabuchi et al., 1989; Kurosaka et al., 1991).

Importantly from a neurological perspective, partial loss of ApoE seems to be tolerated as suggested by a study describing heterozygote carriers of other loss-of-function APOE variants who remained 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.

A227_E230del was absent from the gnomAD variant database (v2.1.1, June 2022).

Biological Effect

A227_E230del is a 10-nucleotide deletion predicted to cause a frameshift introducing a stop codon at amino acid 247. As noted above, in homozygous form, it results in the near elimination of ApoE protein.

The effect of this variant on the central nervous system is unknown. ApoE is involved in multiple brain functions, including  metabolizing and transporting lipids to neurons, synaptogenesis, axonal regeneration, and neural stem cell maintenance and differentiation (for reviews see Koutsodendris et al., 2021; Raulin et al., 2022).

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 APOE loss-of-function variants suggests a 50 percent reduction is tolerated 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).

Although not in the context of this variant, the biological effects of ApoE loss have been studied extensively in Apoe knockout mice, one of the most widely used preclinical models of atherosclerosis (see e.g., Getz et al., 2016; Oppi et al., 2019).

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References

Mutations Citations

1. APOE W5Ter
2. APOE c.237-1A>G
3. APOE W228Ter
4. APOE C130R (ApoE4)

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Feussner G, Dobmeyer J, Gröne HJ, Lohmer S, Wohlfeil S. A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet. 1996 Feb;58(2):281-91. PubMed.
2. Feussner G. Severe xanthomatosis associated with familial apolipoprotein E deficiency. J Clin Pathol. 1996 Dec;49(12):985-9. PubMed.
3. 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.
4. 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.
5. 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.
6. Koutsodendris N, Nelson MR, Rao A, Huang Y. Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annu Rev Pathol. 2022 Jan 24;17:73-99. Epub 2021 Aug 30 PubMed.
7. Raulin AC, Martens YA, Bu G. Lipoproteins in the Central Nervous System: From Biology to Pathobiology. Annu Rev Biochem. 2022 Jun 21;91:731-759. Epub 2022 Mar 18 PubMed.
8. 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.
9. 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.
10. Getz GS, Reardon CA. ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis. J Lipid Res. 2016 May;57(5):758-66. Epub 2016 Mar 25 PubMed.
11. Oppi S, Lüscher TF, Stein S. Mouse Models for Atherosclerosis Research-Which Is My Line?. Front Cardiovasc Med. 2019;6:46. Epub 2019 Apr 12 PubMed.

Other Citations

1. E98Nfs

Further Reading

No Available Further Reading