Overview

Clinical Phenotype: Hyperlipoproteinemia Type III, Blood Lipids/Lipoproteins
Reference Assembly: GRCh37/hg19
Position: 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, which in homozygous form nearly abrogates ApoE in plasma, 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 proband had no apparent neurological or immune-related symptoms. (Of note, the neurological phenotype associated with a different mutation resulting in ApoE deficiency, E98Nfs, has been described).

The proband, a 48-year-old white woman, had ApoE levels in plasma that were approximately 4 percent of normal. Moreover, the detectable protein was truncated, as expected by the stop codon predicted to essentially eliminate the C-terminal domain of ApoE. The proband had elevated cholesterol, elevated triglycerides, and an elevated 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). 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.

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

Consistent with the findings described for the homozygote carrier, other patients with ApoE deficiency have been diagnosed with HLPP3, with unique alterations of their blood lipid and lipoprotein profiles (see e.g., c.237-1A>G, E98Nfs, A227_E230del, and G49Vfs; Mabuchi et al., 1989; Kurosaka et al., 1991). Despite the similarities, however, important variations have been reported. For example, while in some cases HLPP3 has been severe with dramatic alterations in blood lipids accompanied by lipid deposits under the skin and/or in the cornea (e.g., E98Nfs), in others, as in the case of the W228Ter proband, the phenotype was surprisingly mild.

Biological Effect

As described above, this mutation generates a truncated protein missing the C-terminal domain and, in homozygous form, nearly eliminates ApoE from plasma. 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).

The authors speculated that the truncated species is either less stable than full-length ApoE, and/or has a reduced ability to bind lipids which could explain her low plasma ApoE levels. Alternatively, the mutant protein may be degraded intracellularly because of impaired cytoplasmic transport.

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). However, how much a loss of ApoE function can contribute to AD pathology and related neurological disorders remains uncertain (Belloy et al., 2019). In general, reducing or eliminating ApoE in mouse models of amyloid deposition appears to reduce amyloid accumulation, but selectively reducing ApoE in astrocytes, microglia, or neurons suggests cell type-specific effects that can be beneficial, neutral, or harmful (see Biological Effects in E98Nfs).

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).

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

Mutations Citations

1. APOE E98Nfs
2. APOE c.237-1A>G
3. APOE A227_E230del
4. APOE G49Vfs

Paper Citations

1. 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.
2. 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.
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. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.

Further Reading

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