Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146—gln) variant results in a dominant mode of inheritance.
Open accessAbstract
As determined by isoelectric focusing, most patients with familial dysbetalipoproteinemia (FD) exhibit the homozygous apolipoprotein (apo) E2E2 phenotype. Only rarely does FD develop in the more common heterozygous phenotypes E3E2 or E4E2. In fact, only 1 to 4% of the E2E2 homozygotes will develop FD. We wondered whether this reduced penetrance of FD in E2E2 homozygotes could be due to additional heterogeneity in the APOE*2 allele. In the literature a number of different mutations causing an E2 isoelectric focusing variant have been described. To study the genetic heterogeneity of the APOE gene, hybridization of enzymatically amplified genomic DNA with mutation-specific oligonucleotide probes was applied. All FD patients (n = 40) with the E2E2 phenotype appeared to be homozygous for the common E2(arg158----cys) mutation. However, all three unrelated patients with the E3E2 phenotype exhibited the rare E2(lys146----gln) mutation due to an A----C substitution at nucleotide position 3,847 of the APOE gene. This mutation was not found among normolipidemic individuals with the E2E2 (n = 13) or E3E2 phenotype (n = 120) selected from a random population sample. Family studies of the three probands heterozygous for the E*2(lys146----gln) allele showed that this rare allele predisposes to FD with high penetrance. We conclude that FD is a genetically heterogeneous disease entity, displaying a recessive mode of inheritance with strongly reduced penetrance in case of the common E2(arg158----cys) variant and with a dominant mode of inheritance with high penetrance in case of the rare E2(lys146----gln) mutant. It should be noted that in this dominant form presymptomatic diagnosis is possible.
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Other rare apoE variants such as apoE3-Leiden and apoE2(Lys1463 Gln) can also cause dysbetalipoproteinemia.
“Other rare apoE variants such as apoE3-Leiden and apoE2(Lys1463 Gln) can also cause dysbetalipoproteinemia (122, 123).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [122]
Certain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.
“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [10]
Some rare APOE variants that cause familial type III HLP were found to exhibit a dominant mode of inheritance.
“Some of these rare APOE variants that cause familial type III HLP were found to exhibit a dominant mode of inheritance45, 46).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [45]
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- Authors
- Smit, M., de Knijff, P., van der Kooij-Meijs, E., Groenendijk, C., van den Maagdenberg, A., Gevers Leuven, J., Stalenhoef, A., Stuyt, P., Frants, R., & Havekes, L.
- Affiliations
- Leiden University (NL)
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 1990-01
- Volume
- 31
- Issue
- 1
- Pages
- 45-53
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2187552100
- Cited by
- 74
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 4 · 2021: 1 · 2020: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 8.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- familial dysbetalipoproteinemia, APOE gene, genetic heterogeneity, apolipoprotein E, dominant inheritance, incomplete penetrance, recessive inheritance, genotype-phenotype correlation, presymptomatic diagnosis
- MeSH terms
- Alleles, Amino Acid Sequence, Apolipoproteins E, Base Sequence, DNA, Female, Genes, Dominant, Genotype, Homozygote, Humans, Hyperlipoproteinemia Type III, Male, Molecular Sequence Data, Pedigree, Genetic Variation, Apolipoprotein E2
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