Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45412083 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 54-year-old South Korean man with early onset Alzheimer’s disease (Bagaria et al., 2022). His symptoms included memory loss, executive dysfunction, and language impairment. Two brain MRI images taken 19 months apart revealed progressive brain atrophy, mostly in the frontotemporal cortex, the medial temporal lobe, and the basal ganglia, with an increase in cerebral aqueduct size. Measurement of AD biomarkers in cerebrospinal fluid revealed very low levels of Aβ42, suggesting severe amyloid pathology. Interestingly, total tau and phosphorylated tau levels were normal. The carrier died a few months after his second MRI from pneumonia preceded by a heatstroke.

The mutation was identified by whole exome sequencing, which also revealed an absence of known pathogenic variants in AD genes APP, PSEN1, and PSEN2, and in AD risk genes SORL1, ABCA7, and CLU. Known pathogenic and risk variants associated with other neurological diseases, including Parkinson’s disease, frontotemporal dementia, and prion disease, were also absent.

The proband’s mother had been diagnosed with subcortical ischemic vascular dementia. Information about his deceased father was unavailable. His two siblings, one older and one younger, were unaffected at the time of the study.

The variant was absent from public variant databases including gnomAD, 1000 Genomes, ExAC, and the Korean reference genome database (KRGDB).

Biological Effect

The biological effect of this variant is unknown, but it substitutes an evolutionarily conserved amino acid and several in silico algorithms predicted it is damaging (Bagaria et al., 2022). The bulkiness and hydrophobicity of proline is less than that of leucine, and it was expected to introduce a kink in the fourth N-terminal alpha-helix where it resides. Interactions between amino acids, including both short- and long-range interactions, were predicted to be altered, with some being disrupted and new ones being formed.

Moreover, several computational programs, including Mutation Taster, PolyPhen2, and SIFT, predicted L177P is deleterious. Consistently, its PHRED-scaled CADD score (23.9), which integrates diverse information in silico, was above the commonly used threshold of 20 used to predict deleteriousness (CADD v.1.6, June 2022).

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References

Paper Citations

1. Bagaria J, Moon Y, Bagyinszky E, Shim KH, An SS, Kim S, Han SH. Whole Exome Sequencing Reveals a Novel APOE Mutation in a Patient With Sporadic Early-Onset Alzheimer's Disease. Front Neurol. 2022;13:899644. Epub 2022 Jun 10 PubMed.

Further Reading

No Available Further Reading