Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa
Position: (GRCh38/hg38):Chr19:44905632 G>C
Position: (GRCh37/hg19):Chr19:45408889 G>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

This variant, located in the APOE promoter region, was identified in a French patient in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). The carrier had elevated low-density lipoprotein (LDL) cholesterol in blood and was diagnosed with autosomal dominant hypercholesterolemia, also known as hyperlipoproteinemia type IIa (HLPP2a). They did not carry mutations in the genes most commonly associated with HLPP2a—LDLR, PCSK9, APOB—but their weighted polygenic risk score was high (decile X), indicating a strong probability that multiple genes underlie the condition. Their APOE genotype was APOE3/E4 and they had a family history of dyslipidemia.

The variant was absent from the gnomAD variant database.

Biological Effect

The biological effect of this variant is unknown, but it is in the APOE promoter (Paik et al., 1988), within the HuC functional domain, spanning nucleotides -366 to -101 (Maloney et al., 2007). HuC acted as a negative regulatory element in a reporter assay using uninduced human neuronal cells and as a positive regulatory element in uninduced human glial cells. Interestingly, the corresponding mouse sequence (which did not overlap completely with the human sequence) had no apparent effect in neuronal cells and a negative effect in glial cells.

This variant's PHRED-scaled CADD score was 10.31 predicted to be among the top 10 percent of the most deleterious substitutions in the human genome (Abou Khalil et al., 2022). Note that some classifications use 20 as a threshold score (corresponding to the top 1 percent) for predicting a damaging effect.

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References

Paper Citations

1. Abou Khalil Y, Marmontel O, Ferrières J, Paillard F, Yelnik C, Carreau V, Charrière S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrié A, Rabès JP, Varret M. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci. 2022 May 21;23(10) 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