Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
Expected Protein Consequence: Missense
Codon Change: ACT to -
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was reported in a German individual with high triglyceride levels and a low ratio of apolipoprotein B to total cholesterol, features characteristic of hyperlipoproteinemia type III (HLPP3), a condition that often leads to early onset atherosclerosis and heart disease (Evans et al., 2013). Of note, the nucleotide sequence of the substitution was not reported.

Biological Effect

The biological effect of this variant is unknown. Of potential relevance to Alzheimer’s disease, however, a synthetic mutant at this residue expected to disrupt its glycosylation, T212A, has been studied for its ability to bind amyloid β. It was initially reported to have no effect on ApoE binding to Aβ40 (Aleshkov et al., 1999), but a subsequent study found reduced avidity for Aβ42 (Sugano et al., 2008).

T212 is glycosylated in both plasma (10 percent) and cerebrospinal fluid (27 percent) (Flowers et al., 2020). The glycosylation was predicted to have little or no effect on the conformational changes required for receptor binding.

Evans and colleagues predicted T212S is benign based on in silico analysis using the algorithm Polyphen (Evans et al., 2013).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Evans D, Beil FU, Aberle J. Resequencing the APOE gene reveals that rare mutations are not significant contributory factors in the development of type III hyperlipidemia. J Clin Lipidol. 2013 Nov-Dec;7(6):671-4. Epub 2013 May 25 PubMed.
2. Aleshkov SB, Li X, Lavrentiadou SN, Zannis VI. Contribution of cysteine 158, the glycosylation site threonine 194, the amino- and carboxy-terminal domains of apolipoprotein E in the binding to amyloid peptide beta (1-40). Biochemistry. 1999 Jul 13;38(28):8918-25. PubMed.
3. Sugano M, Yamauchi K, Kawasaki K, Tozuka M, Fujita K, Okumura N, Ota H. Sialic acid moiety of apolipoprotein E3 at Thr(194) affects its interaction with beta-amyloid(1-42) peptides. Clin Chim Acta. 2008 Feb;388(1-2):123-9. PubMed.
4. Flowers SA, Grant OC, Woods RJ, Rebeck GW. O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain. Glycobiology. 2020 Jan 28;30(2):74-85. PubMed.

Further Reading

No Available Further Reading