Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908756 C>-
Position: (GRCh37/hg19):Chr19:45412013 C>-
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: CGC to GCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant, predicted to eliminate ApoE expression or generate a truncated species, was identified in heterozygous form in two members of an indigenous Australian family (Tate et al., 2001). The proband, a 64-year-old woman, suffered from hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, characterized by elevated levels of total cholesterol and very low-density lipoprotein (VLDL) cholesterol. Although patients with this condition often have cardiovascular disease, she did not.

As assessed by isoelectric focusing, the proband had ApoE corresponding to the R176C (APOE2) allele and her son had ApoE corresponding to the C130R (APOE4) allele, with no apparent shared isoform. The paradox was resolved after restriction enzyme analysis and DNA sequencing indicated that, in fact, they both also carried an APOE3 allele but the presence of the R154Afs mutation yielded a null phenotype in the isoelectric focusing gel.

Interestingly, the proband’s 49-year-old son had a normal blood lipid profile. The authors speculated that the proband’s ApoE2 allele, which binds very poorly to low-density lipoprotein receptors (LDLRs), contributed to the HLPP3 phenotype. Indeed, heterozygous carriers of other mutations also coding for truncated ApoE species, W5Ter, W38Ter, and E114Gfs, were reported to suffer from HLPP3 or HLPP3-like conditions when carrying APOE2, but not APOE3, on their other chromosome.

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 variants were present on the same chromosome as the major AD risk variant C130R (APOE4), they appeared to decrease AD risk.

R154Afs was absent from the gnomAD variant database (v2.1.1, July 2021).

Biological Effect

This mutation is a deletion of a cytosine in the highly conserved R154 codon (Frieden 2015), which results in a transcript coding for a 250 amino acid-long protein. No mutant ApoE band was observed in the VLDL isoelectric focusing pattern from the two carriers (Tate et al., 2001). The presence of mutant ApoE in serum was not assessed.

The biological effects of this variant are unknown. In the central nervous system, 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).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)
3. APOE W5Ter

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

1. Tate JR, Hoffmann MM, Lovelock PK, Kesting JB, Shaw JT. Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian. Ann Clin Biochem. 2001 Jan;38(Pt 1):46-53. PubMed.
2. 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.
3. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
4. 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.
5. 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.
6. 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.
7. 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. W38Ter

Further Reading

No Available Further Reading