Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44908984 G>A
Position: (GRCh37/hg19):Chr19:45412241 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs567353589
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

Although globally very rare, this variant is relatively frequent in two populations in Ethiopia. It appears to have mild effects, if any, on its carriers’ health, yet has been reported to have in vitro effects on binding, internalization, and degradation of lipid-transporting particles. 

E230K was first reported in heterozygous form in a 23-year-old Turkish man with a kidney disorder known as nephrotic syndrome, and severely altered blood lipids, with a diagnosis of combined hyperlipidemia (Feussner et al., 1996). The association of the variant with these conditions was deemed unlikely, however, because other carriers from the same family were mostly unaffected. The kidney disease, which included deposition of serum amyloid A protein in the proband’s kidneys by age 10, could have been caused by another genetic factor inherited from the father who died from terminal renal failure at age 37. Although the father’s genotype was unknown, he was unlikely to be a carrier since the proband’s mother was identified as a carrier. Moreover, the proband’s abnormal blood lipid profile was thought to be secondary to the kidney disease.

The variant was identified at the protein level after isoelectric focusing of the very-low density lipoprotein (VLDL) fraction of the proband’s blood revealed ApoE3 plus an unusual ApoE band migrating to a more basic position than the common isoform C130R (ApoE4). Based on this, the species was named ApoE5 and subsequent genetic analyses revealed it harbored the E230K substitution on an APOE3 backbone. Of note, the protein had been identified by isoelectric focusing before in an Italian individual with a normal blood lipid profile (Corbo et al., 1995), but its nucleotide sequence was unknown until years later (Scacchi et al., 2003). 

Genetic analysis of 26 relatives of the Turkish proband revealed six heterozygotes, including the proband’s mother, and two homozygotes in the family (Feussner et al., 1996). These carriers had only slightly higher triglycerides and lower high-density lipoprotein (HDL) cholesterol than the non-carriers, but the alterations were not statistically significant. None of the carriers had signs of cardiovascular disease.

A subsequent study identified the variant in two unrelated Amhara and two unrelated Oromo individuals from Ethiopia, as well as in six relatives of two of these individuals, suggesting a frequency of 0.012 and 0.013, respectively (Scacchi et al., 2003). As in the Turkish proband, the variant was always found on an APOE3 background, and as in the Turkish family, the variant was not tied to abnormal lipid or apolipoprotein profiles in blood.

The variant was absent from 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 European ancestry (v2.1.1, June 2022). Interestingly, phylogenetic analyses show that Ethiopians are more closely related to populations of the Mediterranean basin (including Turkey and Italy) than to other populations in Africa (Scacchi et al., 2003).

Biological Effect

VLDL particles isolated from an E230K homozygote bound more effectively to the surface of cultured fibroblasts than those from a non-carrier but were internalized and degraded to a lesser extent (Feussner et al., 1996). The difference in binding was not directly attributable to cell surface receptors for low-density lipoprotein (LDL), however, because competition assays using labeled LDL showed no differences between the mutant and wildtype particles.

The authors suspected the difference might be due to heparin binding since, although E230 is not part of ApoE’s major heparin binding site, it is in a region with affinity for the proteoglycan. Indeed, they found that mutant and wildtype VLDL particles bound to cells lacking proteoglycans to a similar extent. Moreover, mutant VLDL particles bound heparin 22 percent more strongly than wildtype VLDL on a heparin-Sepharose column.  The authors hypothesized that this tighter binding could delay the transfer of lipoprotein particles on the cell surface from proteoglycans to receptors that trigger endocytosis.

This variant’s PHRED-scaled CADD score, which integrates diverse information in silico was 13.84, below the commonly used threshold of 20 used to predict deleteriousness (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE C130R (ApoE4)

Paper Citations

1. Feussner G, Scharnagl H, Scherbaum C, Acar J, Dobmeyer J, Lohrmann J, Wieland H, März W. Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res. 1996 Aug;37(8):1632-45. 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. 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