Overview

Position: (GRCh38/hg38):Chr19:44908960 C>A
Position: (GRCh37/hg19):Chr19:45412217 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1181840153
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to AAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This rare variant has been found in five individuals homozygous for the AD risk allele C130R (APOE4), with no reported cognitive deficiency. Neurological assessments are available for one case, an Australian Caucasian man who participated in the Australian Imaging, Biomarker and Lifestyle (AIBL) study (Roberts et al., 2023). The carrier was cognitively healthy at age 82 as measured by the Mini-Mental State Exam (MMSE). He had brain amyloid buildup, but it had begun late in life as assessed by eight amyloid PET scans across 14 years.

The encoded protein of this variant was first identified by isoelectric focusing in blood samples isolated from individuals in southern Italy (Corbo et al., 1995) and Ethiopia (Corbo et al., 1999). It was called ApoE5 because it migrated beyond ApoE4 due to its basic charge. Sequencing of the variant revealed two variants on the same chromosome: APOE4 and Q222K (Scacchi et al., 2003). Genetic analysis of individuals from the previous studies revealed three carriers in an Oromo family in Ethiopia and one carrier in southern Italy. All carriers had normal blood lipid profiles.

The variant was absent from 89 Amhara individuals in Ethiopia, 80 Benin individuals in West Africa (Scacchi et al., 2003), and was found in only two heterozygotes in the gnomAD variant database, one of unknown ancestry and another of Latino/Admixed American ancestry (v2.1.1, June 2022). Interestingly, phylogenetic analyses suggest Ethiopians are more closely related to populations of the Mediterranean basin than to other populations in Africa, offering a potential explanation for the presence of the variant in Italy and Ethiopia (Scacchi et al., 2003).

Biological Effect

Q222K on an APOE4 backbone failed to form complexes as assessed by Western blots under either disulfide-reducing or non-reducing conditions. This was in contrast to ApoE3 and R176C (ApoE2) which form homodimers as well as complexes with ApoAII (Roberts et al., 2023). However, the effect of the Q222K substitution remains unclear because the ApoE4 allele is itself deficient at mediating these interactions.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was only 10, well below the commonly used threshold of 20 to predict deleteriousness (CADD v.1.6, June 2022).

Based on the Australian carrier who, despite being homozygous for ApoE4, was cognitively stable at an advanced age and had only a late-life increase in brain amyloid, Roberts and colleagues suggested Q222K may be protective, or at least not deleterious (Roberts et al., 2023).

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. APOE R176C (ApoE2)

Paper Citations

1. Roberts BR, Laffoon SB, Roberts AM, Porter T, Fowler C, Masters CL, Dratz EA, Laws SM. Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study. J Alzheimers Dis Rep. 2023;7(1):165-172. Epub 2023 Feb 24 PubMed.
2. Corbo RM, Scacchi R, Mureddu L, Mulas G, Alfano G. Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique. Comparison with frequency data of other European populations. Ann Hum Genet. 1995 Apr;59(2):197-209. PubMed.
3. Corbo RM, Scacchi R, Rickards O, Martinez-Labarga C, De Stefano GF. An investigation of human apolipoproteins B and E polymorphisms in two African populations from Ethiopia and Benin. Am J Hum Biol. 1999;11(3):297-304. PubMed.
4. Scacchi R, De Stefano GF, Ruggeri M, Corbo RM. Genetic variation atapolipoprotein E locus in Ethiopia: an E5 variant corresponds to two different mutant alleles: E*5 (Glu212Lys) and E*5 (Gln204Lys; Cys112Arg). Hum Biol. 2003 Apr;75(2):293-300. PubMed.

Further Reading

No Available Further Reading