Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908531 A>G
Position: (GRCh37/hg19):Chr19:45411788 A>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Reference Isoform: APOE Isoform 1
Genomic Region: intron 3

Findings

In homozygous form, this intronic variant results in nearly complete elimination of ApoE protein. 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.

The phenotype associated with this variant was first described in an African American family from a rural community in Virginia in which several members had ApoE deficiency in plasma and severe hyperlipoproteinemia type III (HLPP3) (Ghiselli et al., 1981). HLPP3, also known as familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease. It is most often caused by R176C (APOE2) homozygosity.

The proband was a 60-year-old woman with lipid deposits known as tubo-eruptive xanthomas on her elbows and knees, bouts of severe chest pain, and a narrowing of a coronary artery as assessed by angiography. While the proband’s mother remained healthy at age 86, her father had xanthomas and died from a myocardial infarction at age 62. Also, three of the proband’s seven siblings had xanthomas, and two who were tested at ages 46 and 48, were found to have HLPP3. All three individuals diagnosed with HLPP3 lacked detectable ApoE in plasma. Compared to most patients with HLPP3, the affected members had lower plasma triglyceride levels, higher low-density lipoprotein (LDL) cholesterol levels, and substantially higher ratios of very-low density lipoprotein (VLDL) to triglycerides. Also, their intermediate-density lipoprotein (IDL) and LDL were abnormal, containing lipoproteins ApoA-IV and ApoB (B-48) which normally don’t form part of these particles. Of note, other patients with ApoE deficiency have been diagnosed with HLPP3, with lipid and lipoprotein profiles that differ somewhat from the disorder’s typical phenotype (E98Nfs, A227_E230del, and W228Ter; also, Mabuchi et al., 1989; Kurosaka et al., 1991).

Subsequent genetic analyses of the proband revealed she carried a splice site mutation (Cladaras et al., 1987) in homozygous form (Lohse et al., 1992; P. Lohse, unpublished data).  Parental consanguinity was suspected, but could not be confirmed (Zannis et al., 1985).

This variant was absent from the gnomAD variant database (v2.1.1, Sep 2022).

Biological Effect

Studies of primary cultures of the proband’s monocytes/macrophages revealed low APOE mRNA levels: 50 (Zannis et al., 1985) or 1-3 (Anchors et al., 1986) percent of normal. Although Anchors and colleagues found no difference in the size of the mRNAs, Zannis and co-workers reported two mRNA species with abnormal molecular weights (Zannis et al., 1985). ApoE protein production in the cultured cells was reported as decreased (Anchors et al., 1986) or undetectable (Zannis et al., 1985).

Cloning and sequencing of the proband’s APOE helped clarify these in vitro findings, revealing an A to G substitution in the acceptor splice site of the third intron (Cladaras et al., 1987). The aberrant splicing caused by the mutation resulted in two mRNAs: one including the entire third intron and one including only 53 nucleotides at its 3’ end. Stop codons in both species generated truncated ApoE peptides (10 kDa) undetectable by polyclonal antibodies. This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 33, suggesting a deleterious effect (CADD v.1.6, Sep 2022).

The effect of this variant on the central nervous system is unknown, but 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). Interestingly, the cognitive health of several aged, heterozygous carriers of other loss-of-function APOE variants suggests at least 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 systemic 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 R176C (ApoE2)
3. APOE A227_E230del
4. APOE W228Ter

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Ghiselli G, Schaefer EJ, Gascon P, Breser HB Jr. Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science. 1981 Dec 11;214(4526):1239-41. 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. Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G, Zannis VI. The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem. 1987 Feb 15;262(5):2310-5. PubMed.
5. 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.
6. Zannis VI, Ordovas JM, Cladaras C, Cole FS, Forbes G, Schaefer EJ. mRNA and apolipoprotein E synthesis abnormalities in peripheral blood monocyte macrophages in familial apolipoprotein E deficiency. J Biol Chem. 1985 Oct 25;260(24):12891-4. PubMed.
7. Anchors JM, Gregg RE, Law SW, Brewer HB Jr. ApoE deficiency: markedly decreased levels of cellular ApoE mRNA. Biochem Biophys Res Commun. 1986 Jan 29;134(2):937-43. PubMed.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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