Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Nephrotic Syndrome
Reference Assembly: GRCh37/hg19
Position: Chr19:45411053_45411054 AG>-
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: GAG to GCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This mutation, predicted to eliminate ApoE expression, was identified in heterozygous form in a Spanish family. The proband, a female child, had very high triglyceride levels and elevated ApoB levels in serum, as well as nephrotic syndrome, a kidney disorder characterized by protein in the urine (Corredor-Andrés et al., 2018). Her mother and grandmother had triglyceride levels that were slightly increased. Suspecting a genetic disorder associated with ApoE, hyperlipoproteinemia type III (HLPP3), the authors sequenced the APOE gene. This revealed the girl carried the common APOE alleles APOE3 and R176C (APOE2), as well as a deletion of two nucleotides in exon 3 on the same chromosome as the APOE3 allele. The deletion, together with the APOE2/E3 genotype, was also identified in the proband’s mother, sister, and maternal grandmother. The mutation was absent from the gnomAD variant database.

Of note, two similar pediatric cases, with nephrotic syndrome and very high triglyceride levels, were reported in children homozygous for APOE2, a genotype associated with HLPP3 (Ellis et al., 1995). Also, heterozygote carriers of other mutations coding for truncated ApoE species in the presence of an APOE2 allele (e.g., W38Ter, R154Afs, W5Ter, and E114Gfs) have been diagnosed with HLPP3.

Biological Effect

This mutation causes a frameshift resulting in an mRNA coding for a 61-amino acid truncated protein predicted to be degraded by nonsense-mediated mRNA decay. Its biological effect is unknown, but together with ApoE2, which binds very poorly to low-density lipoprotein receptors (LDLRs), it is expected to substantially reduce ApoE functionality.

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). Of note, the cognitive health of several aged, heterozygous carriers of other APOE loss-of-function variants suggests a 50 percent loss 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 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).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE W38Ter
3. APOE W5Ter

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

Paper Citations

2. Ellis D, Orchard TJ, Lombardozzi S, Yunis EJ, McCauley J, Agostini R, Diamond JR. Atypical hyperlipidemia and nephropathy associated with apolipoprotein E homozygosity. J Am Soc Nephrol. 1995 Oct;6(4):1170-7. PubMed.
3. 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.
4. 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.
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.

Other Citations

1. R154Afs

Further Reading

No Available Further Reading