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Cited by 88Lipid metabolism and disordersLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3.

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Havel, R J, Kotite, L, Kane, J P, Tun, P, Bersot, T·1983·Journal of Clinical Investigation
DOI 10.1172/jci110978PMC PMC1129193
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Abstract

Familial dysbetalipoproteinemia has been reported to be associated uniquely with an apolipoprotein E phenotype (E2/2) that occurs in approximately 1% of all persons. We have observed the typical clinical and biochemical characteristics of this disorder in five members of a family, in all of whom the apolipoprotein E phenotype, as determined by isoelectric focusing electrophoresis, is E3/3. The disorder is present in three generations of the family: the proband, her mother, and three of the proband's five children. The proband's husband, father of all five children, also has apolipoprotein E phenotype E3/3, as do his two unaffected children. As in normal persons with phenotype E3/3, the apolipoprotein E of affected members appears to have a single residue of cysteine. When incorporated with egg lecithin into discoidal complexes, the apolipoprotein E from affected members was taken up normally into perfused livers of estradiol-treated rats, in which a high level of LDL receptors is expressed. When isoelectric focusing electrophoresis was carried out over a narrow range of pH (5-7), each of the apolipoprotein E isoforms of affected members was observed as a doublet, even after reduction of dimers of the protein with 2-mercaptoethanol and treatment with neuraminidase to minimize the content of sialylated forms of the protein. Doublets were also observed in the apolipoprotein E-2 of patients with classical dysbetalipoproteinemia, but only in the affected members of the family with atypical dysbetalipoproteinemia were the components of the doublets equally prominent. As in classical dysbetalipoproteinemia, both apolipoprotein B-100 and B-48 were present in the very low density lipoprotein fraction of plasma obtained in the postabsorptive state, indicating that remnantlike lipoproteins of both hepatic and intestinal origin accumulate. This observation, together with available evidence on the structural and functional heterogeneity of human apolipoprotein E, lead us to suggest that the disorder in this family is caused by one or two structurally abnormal forms of apolipoprotein E that contain a single residue of cysteine.

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  • Rare APOE variants associated with dominant type III HLPs include APOE2 Heidelberg (Arg136Cys), APOE2 Christchurch (Arg136Ser), APOE2 (Arg142Cys), APOE2 (Arg142Leu), APOE2 (Lys146Gln), and APOE1 Harrisburg (Lys146Glu).

    “Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)47), APOE2 Christchurch (Arg136Ser)26, 48), APOE2 (Arg142Cys)49, 50), APOE2 (Arg142Leu)51), APOE2 (Lys146Gln)45), and APOE1 Harrisburg (Lys146Glu)52, 53) (Table 2, Fig.5).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [50]

    The clinical-features and discussion passages describe familial dysbetalipoproteinemia across three generations and suggest that an abnormal apo E may be involved. They do not identify an APOE2 Lys146Gln substitution, which is the specific variant this citation is attached to; searches for Lys146Gln and position 146 found no such identification in our copy. (LLM, conf=0.78)

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  • Heterozygous patients with a dominant form of type III HLP carrying the ε3 allele and a mutant allele were described in 1983.

    “Heterozygous patients with a dominant form of type III HLP carrying the ␧ 3 allele and a mutant allele were described in 1983 ( 28 ).”

    From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [28]

    The Introduction (page not provided) describes a 1983 study of familial dysbetalipoproteinemia with an E3/3 phenotype that appeared across three generations and had characteristics of a dominant trait. The discussion (page not provided) considers a normal E-3 allele in affected children but also raises the possibility of two functionally defective E-3 alleles. It does not establish that the patients were heterozygous for an ε3 allele and a mutant allele. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Individual cases of type III have been observed with the apo E-3/3 phenotype and with apo E deficiency.

    “Individual cases of type III have also been observed in association with the apo E-3/3 phenotype (9) and in an individual with a deficiency of apo E (10).”

    From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [9]

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Research works printed but not linked: 5

  1. Kane, J. P., D. A. Hardman, and H. E. Paulus. 1980. Heterogeneity of apolipoprotein B: isolation of a new R. J. Havel, L. Kotite, J. P. Kane, P. Tun, and T. Bersot species from human chylomicrons. Proc. Natl. Acad. Sci. USA. 77:2465-2469.
  2. Havel, R. J., Y.s. Chao, E. E. Windler, L. Kotite, and L. S. S. Guo. 1980. Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of fa- milial dysbetalipoproteinemia. Proc. Nati. Acad. Sci. USA. 77:4349-4353.
  3. Havel, R. J., J. L. Goldstein, and M. S. Brown. 1980. Lipoproteins and lipid transport. In Metabolic Control and Disease. P. K. Bondy and L. E. Rosenberg, editors. W. B. Saunders Co., Philadelphia. Eighth ed. 393-494.
  4. Kita, T., J. L. Goldstein, M. S. Brown. Y. Watanabe, C. A. Hornick, and R. J. Havel. 1982. Hepatic uptake of chylomicron remnants in WHHL rabbits: a mecha- nism genetically distinct from the low density lipopro- tein receptor. Proc. Nati. Acad. Sci. USA. 79:3623-3627.
  5. Kita, T., M. S. Brown, D. W. Bilheimer, and J. L. Gold- stein. 1982. Delayed clearance of very low density and intermediate density lipoproteins with enhanced con- version to low density lipoprotein in WHHL rabbits. Proc. Natl. Acad. Sci. USA. 79:5693-5697.

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Authors
Havel, R. J., Kotite, L., Kane, J. P., Tun, P., & Bersot, T.
Affiliations
University of California, San Francisco (US)
ORCID
Kane, J P
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1983-07-01
Volume
72
Issue
1
Pages
379-387
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci110978
PMC
PMC1129193
OpenAlex
W2161200077
Cited by
88
References
5
Citations by year
2026: 1 · 2025: 1 · 2019: 1 · 2014: 1 · 2013: 1
FWCI
5.85
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute
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
familial dysbetalipoproteinemia, apolipoprotein E isoforms, cysteine residues, VLDL, apolipoprotein B-100, apolipoprotein B-48, LDL receptor, familial hyperlipidemia, genetic heterogeneity
MeSH terms
Adolescent, Adult, Aged, Animals, Apolipoproteins, Apolipoproteins E, Child, Female, Humans, Hyperlipoproteinemia Type III, Isoelectric Focusing, Lipids, Lipoproteins, Lipoproteins, VLDL, Liver, Male, Middle Aged, Pedigree, Phenotype, Rats, Apolipoprotein E3

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