Mutations

APOE c.-105A>G

Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIb
Position: (GRCh38/hg38):Chr19:44905784 A>G
Position: (GRCh37/hg19):Chr19:45409017 A>G
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 triglycerides in blood and was diagnosed with familial combined hyperlipidemia, also known as hyperlipoproteinemia type IIb. The carrier had a family history of dyslipidemia and their APOE genotype was APOE3/E3.

The variant was absent from the gnomAD variant database (gnomAD v3.1.1, Nov 2021).

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 which spans 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.

The computational algorithm Mutation Taster predicted c.-105A>G is disease-causing (Abou Khalil et al., 2022). Moreover, its PHRED-scaled CADD score (22.7), which integrates diverse information in silico, was above 20, a commonly used threshold to predict deleteriousness.

Last Updated: 05 Dec 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

Protein Diagram

Primary Papers

  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.

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