Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIb
Position: (GRCh38/hg38):Chr19:44905485 A>G
Position: (GRCh37/hg19):Chr19:45408742 A>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1038445539
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, was identified in two unrelated French patients in a cohort of nearly 6,000 unrelated individuals with primary dyslipidemia (Abou Khalil et al., 2022). Both carriers had elevated triglycerides in blood and were diagnosed with familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb. They also both had a family history of dyslipidemia and abnormal lipid deposits: one beneath the skin of the eyelids and/or nearby areas, a condition known as xanthelasma, and the other inside the cornea, a condition known as corneal arcus. Both carriers had APOE3/E4 genotypes.

The variant’s frequency in the gnomAD variant database was 0.00005, including seven heterozygotes, four of Latino/Admixed American ancestry and three of European ancestry (gnomAD v3.1.1, Nov 2021).

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.

This variant's PHRED-scaled CADD score (7.106), which integrates diverse information in silico, was below 20, a commonly used threshold to predict deleteriousness (Abou Khalil et al., 2022).

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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