The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance.
Abstract
Abstract Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C→T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Homozygosity and heterozygosity for apoE3[R145C] are associated with severe type III HLP.
“Homozygosity and heterozygocity for the apoE variant apoE3[R145C] has also been associated with severe type III HLP [30], [31].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [31]
APOE (Arg145Cys) was inherited dominantly with incomplete penetrance and was thought to be dependent on environmental factors.
“APOE (Arg145Cys) was inherited dominantly with incomplete penetrance and was thought to be dependent on environmental factors64, 65).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [65]
R145C is always in phase with APOE ε3 and R150H is always in phase with APOE ε2.
“Prior studies [7][8][9] and Alzheimer Disease Sequencing Project (ADSP) data have shown that R145C is always in phase with ε3 and R150H is always in phase with ε2.”
From Association of African Ancestry–Specific <i>APOE</i> Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [9]
Cites
Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E
Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W., & Agard, D. A. (1991) · Science · doi:10.1126/science.2063194 · Cited by 678 · see citing works
Rall, S. C., Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.15.4696 · Cited by 345 · see citing works
Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R., & Carrell, R. W. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113096 · Cited by 159 · see citing works
de Knijff, P., van den Maagdenberg, A. M., Stalenhoef, A. F., Leuven, J. A., Demacker, P. N., Kuyt, L. P., Frants, R. R., & Havekes, L. M. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115349 · Cited by 100 · see citing works
Wardell, M. R., Weisgraber, K. H., Havekes, L. M., & Rall, S. C. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)30067-5 · Cited by 80 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mahley, R. W., Huang, Y., & Rall, S. C. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32417-2 · Cited by 447 · see citing works
APOE gene variants in primary dyslipidemia
Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Cenarro, A., Etxebarria, A., de Castro-Orós, I., Stef, M., Bea, A. M., Palacios, L., Mateo-Gallego, R., Benito-Vicente, A., Ostolaza, H., Tejedor, T., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3874 · Cited by 100 · see citing works
Le Guen, Y., Raulin, A.-C., Logue, M. W., Sherva, R., Belloy, M. E., Eger, S. J., Chen, A., Kennedy, G., Kuchenbecker, L., O’Leary, J. P., et al. (2023) · JAMA · doi:10.1001/jama.2023.0268 · Cited by 50 · see citing works
Contribution of <i>APOE</i> Genetic Variants to Dyslipidemia
Bea, A. M., Larrea-Sebal, A., Marco-Benedi, V., Uribe, K. B., Galicia-Garcia, U., Lamiquiz-Moneo, I., Laclaustra, M., Moreno-Franco, B., Fernandez-Corredoira, P., Olmos, S., et al. (2023) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.123.318977 · Cited by 40 · see citing works
Georgiadou, D., Chroni, A., Vezeridis, A., Zannis, V. I., & Stratikos, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027037 · Cited by 24 · see citing works
Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
Matsunaga, A., & Saito, T. (2025) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.65393 · Cited by 14 · see citing works
- Authors
- de Villiers, W. J. S., van der Westhuyzen, D. R., Coetzee, G. A., Henderson, H. E., & Marais, A. D.
- Affiliations
- From the MRC/UCT Research Unit for the Cell Biology of Atherosclerosis, Department of Medical Biochemistry (W.J.S. de V., D.R. van der W., G.A.C.), and the Department of Chemical Pathology and Medicine (H.E.H., A.D.M.), University of Cape Town Medical School, Cape Town, South Africa.
- University of Cape Town (ZA)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 1997-05
- Volume
- 17
- Issue
- 5
- Pages
- 865-872
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2141041965
- Cited by
- 41
- References
- 5
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 1 · 2017: 1 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 2
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E2, type III hyperlipoproteinemia, autosomal dominant inheritance, incomplete penetrance, heterozygous carriers, homozygous carriers, dyslipoproteinemia, ischemic heart disease, atherosclerosis, Black population
- MeSH terms
- Adolescent, Adult, Apolipoproteins E, Arginine, Cysteine, Female, Heterozygote, Homozygote, Humans, Hyperlipoproteinemias, Cholesterol, HDL, Male, Middle Aged, Pedigree, Polymorphism, Restriction Fragment Length, Triglycerides, Restriction Mapping, Point Mutation, Sequence Analysis, DNA, Apolipoprotein E2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
