Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908979 G>A
Position: (GRCh37/hg19):Chr19:45412236 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918396
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant results in a substantial, albeit not complete, loss of function (LoF). Like heterozygote carriers of other APOE LoF variants, most W228 heterozygotes appear to be healthy. Twenty heterozygotes identified in the UK Biobank, for example, were controls, ranging in age from 40 to 79 years (Chemparathy et al., 2024). 

In addition, although three carriers were identified in the Alzheimer’s Disease Sequencing Project (ADSP)—two with cognitive impairment—the authors reasoned the variant is unlikely to increase AD risk. One carrier was healthy at age 67, another had mild cognitive impairment at age 73, and the third developed AD dementia at 77. All three were APOE3/E4 heterozygotes. Because high linkage was established between W228Ter and the APOE3 allele, the predicted effect of W228Ter was a selective reduction of ApoE3 levels, leaving ApoE4 levels intact.  In both affected cases, ages at onset were later than the mean age of onset for APOE4 homozygotes (69.73), suggesting W228Ter did not accelerate AD onset.

W228Ter was first identified in a homozygote woman diagnosed with hyperlipoproteinemia type III (HLPP3) (Lohse et al., 1992). The condition, a.k.a. familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease. Neurological data were not reported, but the authors noted the woman, who was 48 years old at the time, had no apparent neurological or immune-related symptoms. Her ApoE levels in plasma were approximately 4 percent of normal and the detectable protein was truncated, as expected by the stop codon predicted to essentially eliminate the C-terminal domain of ApoE.

The homozygote woman also had elevated levels of cholesterol and triglycerides, as well as an increased ratio of very low-density lipoprotein (VLDL) cholesterol to triglycerides, alterations consistent with HLPP3. However, her triglyceride levels were lower and her ratio of VLDL cholesterol to triglycerides was higher than in typical HLPP3 patients. As noted by the authors, similar departures from canonical HLPP3 have been observed in other ApoE deficient patients (e.g., c.237-1A>G, E98fs, and A227_E230del). Also, 10 years of estrogen replacement therapy may have contributed to her altered lipid profile. The proband also had increased concentrations of ApoB-48, a marker for lipoproteins of intestinal origin, indicating a disruption of ApoE-mediated removal by the liver of remnants of lipoprotein carrier particles, chylomicrons, and VLDL. Despite these abnormalities, the proband’s clinical phenotype was mild compared to homozygote patients of other LoF variants, possibly because of W228Ter resulting in only partial LoF (see Biological Effects below).

The variant was also identified in the proband’s son and daughter who were both heterozygotes and had plasma ApoE levels of less than 50 percent of normal. Plasma lipid and lipoprotein cholesterol values of these two carriers, both in their 20s, were within the normal range. Also of note, there was a strong history of hyperlipidemia and premature atherosclerosis in the family. Two paternal uncles of the proband had died in their 60s of myocardial infarction, and a maternal uncle (age 66), an aunt (age 63), a sister (age 50), and a brother (age 46) suffered from hypercholesterolemia.

In addition, W228Ter was found in a Portuguese child with familial hypercholesterolemia (Mariano et al., 2020). It was in heterozygous form and the authors considered it unlikely to be the cause of the child’s condition.

Two heterozygotes of European ancestry were reported in the gnomAD variant database (v2.1.1, June 2022).

Biological Effect

As described above, this variant generates a truncated protein missing the C-terminal domain and, in homozygous form, drastically reduces ApoE levels in plasma (Lohse et al., 1992), and decreases ApoE production and secretion by approximately two thirds in cultured hepatocytes (Chemparathy et al., 2024). Although the truncated protein is predicted to lack lipid-binding and homo-oligomerization regions, it appears to have at least limited ability to bind to lipoprotein particles as indicated by its presence in the homozygote carrier’s VLDL particles (Lohse et al., 1992).

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). Data from this carrier together with heterozygotic carriers of other APOE loss-of-function mutations—W5Ter, Q39Ter, and g.45408560-45410359del—suggests a 50 percent loss of ApoE protein 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 has shown 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).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 31, well above the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, May 2022). It was classified as pathogenic (Mariano et al., 2020) based on guidelines by the American College of Medical Genetics and Genomics (Richards et al., 2015).

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References

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Mutations Citations

1. APOE c.237-1A>G
2. APOE A227_E230del
3. APOE W5Ter
4. APOE Q39Ter
5. APOE g.45408560_45410359del

Paper Citations

1. 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.
2. Lohse P, Brewer HB 3rd, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB Jr. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res. 1992 Nov;33(11):1583-90. PubMed.
3. Mariano C, Alves AC, Medeiros AM, Chora JR, Antunes M, Futema M, Humphries SE, Bourbon M. The familial hypercholesterolaemia phenotype: Monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes. Clin Genet. 2020 Mar;97(3):457-466. PubMed.
4. 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.
5. 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.
6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Other Citations

1. E98fs

Further Reading

No Available Further Reading