Overview

Pathogenicity: Progressive Supranuclear Palsy
Clinical Phenotype: Progressive Supranuclear Palsy
Reference Assembly: GRCh37/hg19
Position: Chr19:45411803 G>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Nonsense
Codon Change: GAG to TAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant, predicted to eliminate functional APOE expression, was identified in heterozygous form in a patient with progressive supranuclear palsy (PSP) in a search for APOE  loss-of-function (LoF) variants (Chemparathy et al., 2024, Aug 2023 conference news). The search included whole-genome and whole-exome sequencing data from 20,856 AD cases and 26,605 older controls in the Alzheimer’s Disease Sequencing Project (ADSP), 448,049 whole-exomes from the UK Biobank, and 478 whole-exomes from the HEX dataset. The carrier, a male participant in the ADSP with an APOE3/E3 genotype, was diagnosed with PSP at age 74 and died at age 77.

This variant was reported in the gnomAD variant database at a frequency of 0.0000014, including two heterozygote carriers, one with African ancestry and the other with European (non-Finnish) ancestry (v4.0.0, Mar 2024).

Neuropathology
The carrier had neuropathology consistent with PSP (Chemparathy et al., 2024). He also had neurofibrillary tangle pathology (Braak stage 3), but no amyloid pathology either in brain parenchyma or in cerebral vessels.

Biological Effect
This mutation is predicted to abrogate the full-length synthesis of ApoE introducing an early stop codon in the APOE coding region. Of note, data from other heterozygote carriers of LoF variants suggest 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 above 20 (35), suggesting a deleterious effect (CADD v.1.7, Apr 2024).

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References

Mutation Data Table Citations

1. APOE Loss of Function Variants 7 Mar 2024

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. 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. Aug 2023 conference news

Further Reading

No Available Further Reading