Overview

Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45408634 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs532314089
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

This variant was reported in a small study in which the APOE genes of 257 Southern Chinese individuals, including 69 AD patients, 83 subjects with mild cognitive impairment (MCI), and 105 cognitively healthy controls, were sequenced (Yee et al., 2021). The variant was found in two AD patients (1.4%), zero MCI patients (0%), and one control (0.5%).

In the gnomAD variant database, c.-488C>A was reported at a frequency of 0.0016, with most carriers having either non-Finnish European ancestry (0.0018 frequency; 27 heterozygotes and one homozygote) or African ancestry (0.017 frequency; 15 heterozygotes) (gnomAD v2.1.1, Oct 2022).

Biological Effect

The biological effect of this variant is unknown, but is in the APOE promoter (Paik et al., 1988), within the HuD functional domain which spans nucleotides -651 to -366 (Maloney et al., 2007). HuD was shown to act as a negative regulatory element in multiple cell types, including neuronal-like rat chromaffin cells (PC12), SK-N-SH neuroblastoma cells, C6 glial cells, and U373 astroctyoma cells. Moreover, c.-488C nucleotide is in a potential binding motif for the transcription factor Early Growth Response Protein 1 (EGR1), and the substitution abolishes the motif (Yee et al., 2021).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 0.26, well below the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, Oct 2022).

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References

Paper Citations

1. Yee A, Tsui NB, Kwan RY, Leung AY, Lai CK, Chung T, Lau JY, Fok M, Dai DL, Lau LT. Apolipoprotein E Gene Revisited: Contribution of Rare Variants to Alzheimer's Disease Susceptibility in Southern Chinese. Curr Alzheimer Res. 2021 Mar 24; PubMed.
2. Paik YK, Chang DJ, Reardon CA, Walker MD, Taxman E, Taylor JM. Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem. 1988 Sep 15;263(26):13340-9. PubMed.
3. Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.

Further Reading

No Available Further Reading