Mature Protein Numbering: R142C

Other Names: ApoE1 Nagoya


Clinical Phenotype: Blood Lipids/Lipoproteins, Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45412031 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs387906567
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4


This mutation was first identified in a family of Salvadoran origin suffering from hyperlipoproteinemia type III (HLPP3), a condition that often leads to early onset atherosclerosis and heart disease (Havel et al., 1983; Rall et al., 1989). The initial study reported five family members spanning three generations who had the typical characteristics of HLPP3, including fat deposits under the skin of the palms of their hands, approximately equal elevations of plasma cholesterol and triglycerides, and the presence of cholesteryl ester-rich lipoprotein particles known as β-very-low-density lipoprotein (β-VLDL) in blood (Havel et al., 1983).

They also presented with a few unusual phenotypes. Several teenage family members had pronounced hyperlipidemia which rarely occurs before adulthood in HLPP3. Also, the authors expected the ApoE proteins of affected individuals to migrate to the position of the common R176C (ApoE2) allele since APOE2 homozygosity is the most common genetic cause of familial HLPP3. Instead, they migrated to the ApoE3 position.

A subsequent study clarified the apparent paradox revealing the presence of the R160C mutation on a C130R (APOE4) backbone (Rall et al., 1989). The two variants together on the same chromosome explained the APOE3-like isoelectric migration of the encoded protein. The authors also reported a dominant pattern of inheritance. Genotyping 10 family members spanning four generations, they found that only the five members suffering from HLPP3 carried the mutation and they were all heterozygotes. Of note, this dominant pattern is also seen in the phenotype of APOE knockout mice expressing human APOE4 with the R160C mutation (Vezeridis et al., 2011).

The variant was also reported in a German individual with high triglyceride levels and a low ratio of apolipoprotein B to total cholesterol, features characteristic of HLPP3 (Evans et al., 2013).

The variant was absent from the gnomAD variant database (v2.1.1, May 2022).

Biological effects

The R160C variant has been reported to cause several functional alterations. Consistent with its location in the receptor-binding region of ApoE, R160C was initially found to be defective at competing with low-density lipoprotein (LDL) for binding to the surface of human fibroblasts, performing about 20 to 25 percent as effectively as ApoE3 (Rall et al., 1989). Subsequent studies confirmed this impairment and showed that the affinity of recombinant R160C complexed with the artifical lipid DMPC was similarly reduced whether it was on an ApoE3 or ApoE4 backbone (Horie et al., 1992).

Somewhat surprisingly, however, R160C’s ability to compete with LDL for cell surface binding proved higher than that of ApoE2 which has a weaker association with HLPP3 characterized by a recessive pattern of inheritance with incomplete penetrance (Bersot et al.1983, Innearity et al., 1986, Chapell, 1989). This suggested that R160C may result in other effects beyond a reduction in receptor binding. Indeed, additional studies showed that, unlike ApoE2, R160C has an extremely low affinity for heparin sulfate proteoglycans (HSPG) as assessed by both cell-based and in vitro binding assays (Horie et al., 1992; Ji et al., 1994a). Subsequent biochemical examinations of ApoE-heparin binding pinpointed R160 as a critical amino acid for this interaction (Libeu et al., 2001, Dong et al., 2001). In addition, R160C was found to be roughly three times more prevalent than wildtype ApoE in very low-density lipoproteins (VLDLs) of R160C heterozygotes, suggesting R160C could have an effect that was greater than expected by the presence of a single mutant allele (Horie et al., 1992, Fazio et al., 1994a).

Also, Veziridis and colleagues suggested that, beyond altering  the receptor-binding and the overlapping HSPG-binding sites, R160C might disrupt ApoE structure resulting in additional effects on lipid metabolism (Vezeridis et al., 2011). Using adenovirus-mediated gene transfer to express R160C in APOE knockout mice, the authors found the mutant increased plasma cholesterol, triglycerides, and ApoE, as well as the levels of immature high-density lipoprotein (HDL) particles, decreased esterification of cholesterol in all lipoprotein fractions, and caused accumulation of ApoE, mostly in VLDL, intermediate-density (IDL) and LDL particles. Of note, ApoE accumulation inhibits lipoprotein lipase and lecithin:cholesterol acyltransferase, enzymes involved in the normal receptor-mediated clearance of triglylceride-rich lipoproteins and the maturation of HDL particles. Moreover, previous observations of transgenic mice overexpressing R160C suggested the mutant protein interferes with hepatic lipase’s ability to enhance the binding and uptake of cholesteryl ester-rich β-VLDL which accumulates in HLPP3 patients (Ji et al., 1994b).

Vezeridis and co-workers proposed these effects might be caused by the disruption of interactions of the N-terminal domain with the C-terminal domain which some suggest shields the ApoE’s receptor-binding region. Although Horie and colleagues found little effect of removing C-terminal amino acids 209-317 on receptor binding in vitro (Horie et al., 1992), Veziridis et al. saw a reduction of in vivo R160C-associated alterations after removal of amino acids 231-317. Thus, R160C may have a direct effect on receptor binding, as well as an indirect effect on ApoE’s conformation. Indeed, a study using FRET and computational simulations to study monomeric ApoE4 predicted R160, in the N-terminal domain, contacts D245, in the C-terminal domain, when the latter is undocked from the N-terminal helix bundle (Stuchell-Brereton et al., 2023).

Also of note, an artificial substitution at this same site, R160A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 more strongly than to ApoE3 or ApoE2 and activates pro-inflammatory pathways (Zhou et al., 2023).

R160 is evolutionarily conserved across 63 mammalian species (Frieden et al., 2015) and R160C’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

Research Models

Several mouse models carrying this mutation have been generated (Fazio et al., 1993, Fazio et al., 1994b, Vezeridis et al., 2011). The mice developed by Veziridis et al. described above were generated by injection of R160C-carrying adenovirus into the bloodstream of APOE knockout mice, with transfection efficiency monitored by mRNA production in the liver (Vezeridis et al., 2011). On the other hand, the transgenic mice generated by Fazio et al. expressed endogenous mouse apoE in all their tissues and the mutant, human gene only in the liver. In these mice, high expressors of the mutant protein developed hyperlipidemia similar to that of HLPP3 patients, including elevated levels of the atherogenic lipoprotein β-VLDL, consistent with the phenotypes observed in the Veziridis mice, but less severe. Low expressors, producing about half the levels of endogenous apoE, showed only a modest increase in VLDL cholesterol.

Last Updated: 15 Feb 2023


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Mutations Citations

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

Paper Citations

  1. . Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest. 1983 Jul;72(1):379-87. PubMed.
  2. . Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant. J Clin Invest. 1989 Apr;83(4):1095-101. PubMed.
  3. . Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4. J Lipid Res. 2011 Jan;52(1):45-56. Epub 2010 Sep 22 PubMed.
  4. . 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.
  5. . The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem. 1992 Jan 25;267(3):1962-8. PubMed.
  6. . Cholesteryl ester accumulation in mouse peritoneal macrophages induced by beta-migrating very low density lipoproteins from patients with atypical dysbetalipoproteinemia. J Clin Invest. 1983 Sep;72(3):1024-33. PubMed.
  7. . Apolipoprotein E is the determinant that mediates the receptor uptake of beta-very low density lipoproteins by mouse macrophages. Arteriosclerosis. 1986 Jan-Feb;6(1):114-22. PubMed.
  8. . High receptor binding affinity of lipoproteins in atypical dysbetalipoproteinemia (type III hyperlipoproteinemia). J Clin Invest. 1989 Dec;84(6):1906-15. PubMed.
  9. . Variable heparan sulfate proteoglycan binding of apolipoprotein E variants may modulate the expression of type III hyperlipoproteinemia. J Biol Chem. 1994 May 6;269(18):13421-8. PubMed.
  10. . New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem. 2001 Oct 19;276(42):39138-44. Epub 2001 Aug 10 PubMed.
  11. . Interaction of the N-terminal domain of apolipoprotein E4 with heparin. Biochemistry. 2001 Mar 6;40(9):2826-34. PubMed.
  12. . Co-expression of cholesteryl ester transfer protein and defective apolipoprotein E in transgenic mice alters plasma cholesterol distribution. Implications for the pathogenesis of type III hyperlipoproteinemia. J Biol Chem. 1994 Dec 23;269(51):32368-72. PubMed.
  13. . Enhanced binding and uptake of remnant lipoproteins by hepatic lipase-secreting hepatoma cells in culture. J Biol Chem. 1994 May 6;269(18):13429-36. PubMed.
  14. . Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.
  15. . LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. Epub 2023 Jan 2 PubMed.
  16. . ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
  17. . Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E. J Clin Invest. 1993 Sep;92(3):1497-503. PubMed.
  18. . Altered lipoprotein metabolism in transgenic mice expressing low levels of a human receptor-binding-defective apolipoprotein E variant. J Lipid Res. 1994 Mar;35(3):408-16. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant. J Clin Invest. 1989 Apr;83(4):1095-101. PubMed.
  2. . Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest. 1983 Jul;72(1):379-87. PubMed.

Other mutations at this position

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