Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and & epsilon;1/lsquo;null genotype‡
Abstract
Abstract. A 60‐year‐old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl‐1). The patient's apo E migrated in the apo El position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo ε l allele and another allele whose product did not appear in the plasma compartment (‘null’ allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endo‐nuclease Taq I identified an adenosine for guanosine (G←A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E l isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo εl allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol‐enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a nonfunctional ‘null’ allele in addition to a probably dominant apo El (Gly 127→Asp, Arg 158→Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.
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Cases of apoE deficiency have been reported, but none included neurocognitive or retinal function studies.
“Cases of apoE deficiency have been reported,4-9 but none included neurocognitive or retinal function studies.”
From Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function (2014) · cites this paper as [7]
A 60-year-old Caucasian male compound heterozygous for APOE1 (Gly127Asp, Arg158Cys) and a nucleotide deletion of guanosine at codon 31 (Gly31fsTer29) had a severe form of familial type III HLP.
“A 60-year-old Caucasian male compound heterozygous for APOE1 (Gly127Asp, Arg158Cys) and a nucleotide deletion of guanosine at codon 31 (Gly31fsTer29) was reported to have a severe form of familial type III HLP (Table 1)37, 38).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [37]
Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes.
“Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [37]
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Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
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- Authors
- FEUSSNER, G., FUNKE, H., WENG, W., ASSMANN, G., LACKNER, K. J., & ZIEGLER, R.
- Affiliations
- Heidelberg University (DE)
- University of Münster (DE)
- Corresponding author
- FEUSSNER, G.
- ORCID
- LACKNER, K. J.
- Venue
- European Journal of Clinical Investigation
- Publisher
- Wiley
- Published
- 1992-09
- Volume
- 22
- Issue
- 9
- Pages
- 599-608
- ISSN
- 0014-2972 (ISSN-L)
- 1365-2362
- OpenAlex
- W1966877648
- Cited by
- 28
- References
- 47
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2012: 1
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Clinical Investigation (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 › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type III hyperlipoproteinemia, apolipoprotein E, compound heterozygosity, premature cardiovascular disease, cysteine residues, sialylation, familial hyperlipidemia, premature stop codon
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Apolipoproteins E, Base Sequence, Centrifugation, Density Gradient, Child, Child, Preschool, Electrophoresis, Polyacrylamide Gel, Female, Genetic Techniques, Genotype, Heterozygote, Humans, Hyperlipoproteinemia Type III, Isoelectric Focusing, Male, Middle Aged, Molecular Sequence Data, Pedigree, Phenotype, Polymorphism, Restriction Fragment Length, Immunoblotting, Cholesterol, VLDL, Gene Expression, Polymerase Chain Reaction, Frameshift Mutation, Point Mutation, Sequence Analysis, DNA
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