Discovery and consequences of apolipoprotein- ε 3Groningen : a G-insertion in codon 95/96 that is predicted to cause a premature stop codon
Open accessAbstract
Background: We found an unexplained, persistent discrepancy between the outcomes of two apolipoprotein-E (apo-E) genotyping methods for a patient with features of familial dysbetalipoproteinaemia (FD). Polymerase chain reaction - restriction fragment length polymorphism resulted in the apo-ε 2 /ε 2 genotype, whereas minisequencing indicated apo-ε 2 /ε 3 . The discrepancy was predicted to derive from a novel mutation. Methods: Sequencing of patient DNA, set-up of a mutation analysis method and establishment of mutation occurrence in 19 family members of the proband and investigation of its association with serum lipid indices. Results: Sequencing demonstrated a G-insertion in codon 95 or 96 ( 95 AAG- 96- GAG- 95 AAG- 96 GGA-G) of the apo-ε 3 allele. The mutation, designated apo-ε 3Groningen , was predicted to cause a frameshift, a premature stop codon at codon 146 (AAGεTAA) and the expression of a truncated apo-E protein, if any. Four family members with the apo-ε 3Groningen were identified. Two family members with apo-ε 3 /ε 3Groningen had serum lipid indices within reference ranges but low-serum apo-E. Three subjects with apo-ε 2 /ε 3Groningen , proband included, had serum cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol levels above the reference ranges. Their electrophoresis pattern showed the classical broad-beta band, indicative of FD. Conclusion: Apo-ε 3Groningen heterozygosity is unlikely to precipitate FD, unless provoked by compound apo-ε 2 heterozygosity or other FD precipitating factors.
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Written from the paper’s full text.
TL;DR
A novel apo-E allele, apo-ε3Groningen, was found as a G-insertion in codon 95/96 of the apo-ε3 allele that explained a persistent apo-E genotyping discrepancy and is predicted to cause a frameshift, premature stop codon at codon 146, and truncated apo-E. In this family, apo-ε3Groningen heterozygosity alone did not appear sufficient to cause familial dysbetalipoproteinaemia, but compound apo-ε2/ε3Groningen carriers showed lipid and electrophoretic features consistent with FD.
Key findings
- Sequencing demonstrated a G-insertion in codon 95 or 96 (95AAG-96GAG-95AAG-96GGA-G) of the apo-ε3 allele, designated apo-ε3Groningen; it was predicted to cause a frameshift, a premature stop codon at codon 146 (AAG-TAA), and expression of a truncated, likely nonfunctional apo-E protein, if any.
- The mutation explained the genotype discrepancy: PCR-RFLP by Reymer et al. gave apo-ε2/ε2 because the apo-ε3Groningen allele was not amplified, whereas minisequencing gave apo-ε2/ε3.
- Four relatives carried apo-ε3Groningen. Two subjects with apo-ε3/ε3Groningen had serum lipid indices within reference ranges but low serum apo-E (7.4 and 12.3 mg/L), while three subjects with apo-ε2/ε3Groningen, including the proband, had serum cholesterol, triglycerides, and calculated LDL-cholesterol above local reference ranges and broad-beta bands on electrophoresis indicative of FD.
- The authors conclude that apo-ε3Groningen heterozygosity is unlikely to precipitate FD unless provoked by compound apo-ε2 heterozygosity or other FD-precipitating factors; homozygosity was not encountered but would most probably precipitate FD without other factors.
Methods
- Case investigation of a patient with features of FD and an unexplained persistent discrepancy between two apo-E genotyping methods; DNA sequencing was used to identify the mutation, and a new allele-specific PCR with a mutation primer was constructed for detection.
- Nineteen family members of the proband were investigated for mutation occurrence, with information on age, medical history, medication, physical examination for xanthomata/palmar striae, and fasting blood samples.
- Serum lipids, HDL-cholesterol, calculated LDL-cholesterol by the Friedewald approximation, serum apo-E by ELISA, lipoprotein electrophoresis, and secondary hyperlipidaemia markers were measured; the mutant primer was also tested in 100 previously tested apo-E genotyping samples, none of which yielded a PCR product.
Limitations
- The paper states that the small number of subjects with apo-ε3Groningen limits statistical analysis and that firm conclusions cannot be drawn from this study.
- The paper states that abnormal serum lipids also occurred in relatives without the truncated apo-E, which may be caused by other familial lipid abnormalities.
- Evident from the text: no homozygotes for apo-ε3Groningen were encountered, and the predicted truncated protein, premature stop codon, and functional consequences were not experimentally confirmed by protein expression or functional assays.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 6 cited sources checked · 0 supported · 0 flagged
- Findingown data
Two family members with apo-e3/e3Groningen had serum lipid indices within reference ranges but low serum apo-E.
“Two family members with apo-e 3 /e 3Groningen had serum lipid indices within reference ranges but low-serum apo-E.”
- Also stated in: § Family investigation · plain
“The two subjects with apo-e 3 /e 3Groningen had serum lipid indices within reference ranges, low serum apo-E and normal lipoprotein electrophoresis patterns”
Quote in the paperSubstantial claim - Also stated in: § Family investigation · plain
- Findingown data
Of the non-apo-e3Groningen carriers, three with the apo-e3/e3 genotype and two with the apo-e2/e3 genotype had lipid indices above the reference values.
“Of the non-apo-e 3Groningen carriers, three with the apo-e 3 /e 3 genotype and two with the apo-e 2 /e 3 genotype had lipid indices above the reference values.”
Quote in the paperNot a substantial claim - Findingnone given
Except for the diabetic subject, none of the investigated relatives had clinical chemical signs of secondary hyperlipidaemia.
“Except for the diabetic subject, none of the investigated relatives had clinical chemical signs of secondary hyperlipidaemia.”
Quote in the paperSubstantial claim - Findingnone given
The patient reported signs of xanthomata and palmar striae from the age of 18 years.
“The patient reported signs of xanthomata and palmar striae from the age of 18 years.”
Quote in the paperNot a substantial claim - Findingown data
Four family members with the apo-e3Groningen allele were identified.
“Four family members with the apo-e 3Groningen were identified.”
- Also stated in: § Family investigation · plain
“We identi¢ed four relatives who carried the apo-e 3Groningen allele.”
Quote in the paperSubstantial claim - Also stated in: § Family investigation · plain
- Findingown data
Three subjects with apo-e2/e3Groningen, including the proband, had serum cholesterol, triglycerides and calculated LDL-cholesterol levels above the reference ranges.
“Three subjects with apo-e 2 /e 3Groningen , proband included, had serum cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol levels above the reference ranges.”
- Also stated in: § Family investigation · plain
“the three subjects with apo-e 2 / e 3Groningen , the proband included, had serum cholesterol, triglycerides and calculated LDL-cholesterol levels above the local reference ranges.”
Quote in the paperSubstantial claim - Also stated in: § Family investigation · plain
- Findingown data
The serum apo-E levels of apo-e2/e3Groningen subjects seemed higher than those of apo-e3/e3Groningen subjects.
“Their serum apo-E levels seemed higher than those of the subjects with apo-e 3 /e 3Groningen .”
Quote in the paperNot a substantial claim - Findingown data
Sequencing demonstrated a G-insertion in codon 95 or 96 (95 AAG-96-GAG-95 AAG-96 GGA-G) of the apo-e3 allele.
“Sequencing demonstrated a G-insertion in codon 95 or 96 ( 95 AAG-96- GAG-95 AAG-96 GGA-G) of the apo-e 3 allele.”
- Also stated in: § The apo-e 3Groningen mutation · boosted
“Sequencing demonstrated a G-insertion in codon 95 or 96 ( 95 AAG-96 GAG-95 AAG-96 GGA-G).”
Quote in the paperSubstantial claim - Also stated in: § The apo-e 3Groningen mutation · boosted
- Findingown data
For a patient with features of familial dysbetalipoproteinaemia (FD), PCR-RFLP apo-E genotyping gave the apo-e2/e2 genotype while minisequencing gave the apo-e2/e3 genotype, a persistent unexplained discrepancy.
“We found an unexplained, persistent discrepancy between the outcomes of two apolipoprotein-E (apo-E) genotyping methods for a patient with features of familial dysbetalipoproteinaemia (FD).Polymerase chain reactionrestriction fragment length polymorphism resulted in the apo-e 2 /e 2 genotype, whereas minisequencing indicated apo-e 2 /e 3 .”
- Also stated in: § Introduction · plain
“We observed an unexplained persistent discrepancy between the outcomes of these apo-E genotyping methods (for a review, see Brouwer et al. 1 ).”
Quote in the paperSubstantial claim - Also stated in: § Introduction · plain
- Interpretationreasoning
If expressed, the truncated apo-E protein would almost certainly be nonfunctional.
“Expression would almost certainly result in a nonfunctional apo-E protein.”
Quote in the paperSubstantial claim - Interpretationown data
The patient was diagnosed with FD at age 49 on the basis of the erroneously found apo-e2/e2 genotype.
“He was diagnosed with FD at the age of 49 years on the basis of the erroneously found apo-e 2 /e 2 genotype (see Results and discussion).”
Quote in the paperSubstantial claim - Interpretationreasoning
The G-insertion mutation explains the discrepancy between the RFLP and minisequencing apo-E genotyping methods.
“The encountered mutation explains the discrepancy between the methods by RFLP and minisequencing.”
Quote in the paperSubstantial claim - Interpretationown data
The profiles of apo-e2/e3Groningen subjects are consistent with those found in FD.
“These pro¢les are consistent with those found in FD.”
Quote in the paperSubstantial claim - Interpretationreasoning
The receptor-binding capacity of the truncated apo-E protein would be low because part of the receptor-binding domain (amino acids 136-158) is altered (136-145) and the remainder is missing (146-158).
“The receptor-binding capacity would be low, since part of amino acids in the receptor-binding domain (i.e.amino acids 136--158) are altered (i.e.amino acids 136--145) and the remainder are missing (146--158).”
Quote in the paperSubstantial claim - Interpretationreasoning
Apo-e3Groningen heterozygosity is unlikely to precipitate FD, unless provoked by compound apo-e2 heterozygosity or other FD-precipitating factors.
“Apo-e 3Groningen heterozygosity is unlikely to precipitate FD, unless provoked by compound apo-e 2 heterozygosity or other FD precipitating factors.”
- Also stated in: § Family investigation · hedged
“The mutation, entitled apo-e 3Groningen , is in its heterozygous form unlikely to precipitate to FD, unless provoked by compound heterozygosity for apo-e 2 or other FD-precipitating factors.”
Quote in the paperSubstantial claim - Also stated in: § Family investigation · hedged
- Interpretationown data
The G-insertion is located on the apo-e3 allele.
“The G-insertion was indirectly proven to be located on the apoe 3 allele because the Reymer RFLP method detected an apo-e 2 but not an apo-e 3 allele.”
- Also stated in: § The apo-e 3Groningen mutation · plain
“Based on these two observations, we designated the mutation to the apo-e 3 allele and entitled it apo-e 3Groningen .”
Quote in the paperSubstantial claim - Also stated in: § The apo-e 3Groningen mutation · plain
- Study design and conductown data
Presence of a PCR product and the apo-e3 restriction fragment pattern was indicative of the presence of the apo-e3Groningen allele.
“Presence of a PCR product and the apo-e 3 restriction fragment pattern was indicative for the presence of the apo-e 3Groningen allele.”
Quote in the paperSubstantial claim - Interpretationreasoning
Homozygosity for apo-e3Groningen, although not encountered in this study, would most probably precipitate FD without the need for other factors.
“Homozygosity, although not encountered in our study, would most probably precipitate FD without the need for other factors.”
Quote in the paperSubstantial claim - Interpretationcitation
The G-insertion causes a mismatch at the 3' end of one RFLP primer used in the Reymer method, preventing that primer from being extended.
“The G-insertion caused a mismatch at the 3 0 end of one of the RFLP primers used in the Reymer method, 4 resulting in the inability of this primer to become extended.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
In subjects heterozygous for truncated apo-E forms, the remaining apo-E protein can maintain adequate remnant clearance, provided that it is functional.
“From these studies, it can be concluded that in subjects who are heterozygous for truncated apo-E forms, the remaining apo-E protein can maintain adequate remnant clearance, provided that it is functional.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 9--11,14--16
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
The truncated apo-E protein lacks the carboxy-terminal region, which is considered to be the lipid-binding domain.
“In addition, the protein lacks the carboxy-terminal region, which is considered to be the lipid-binding domain.8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
The frameshift is predicted to result in a premature stop codon at codon 146 (AAG-TAA).
“The ensuing frameshift due to the 95 AAG-96 GAG -95 AAG-96 GGA-G insertion is predicted to result in a premature stop codon at codon 146 (AAG-TAA) and the expression of a truncated apo-E isoform, if any.”
Quote in the paperSubstantial claim - Interpretationown data
The electrophoretic patterns of subjects with apo-e2/e3Groningen and the subject with apo-e2/e2 in combination with high calculated LDL-cholesterol showed broad-beta bands, indicating that IDL contributed to the calculated LDL.
“The electrophoretic patterns of subjects with apo-e 2 /e 3Groningen and the subject with apo-e 2 /e 2 in combination with high calculated LDLcholesterol showed broad-beta bands, indicating that IDL contributed to the calculated LDL.”
Quote in the paperSubstantial claim - Interpretationreasoning
The mutation is predicted to result in expression of a truncated apo-E protein, if any.
“The ensuing frameshift due to the 95 AAG-96 GAG -95 AAG-96 GGA-G insertion is predicted to result in a premature stop codon at codon 146 (AAG-TAA) and the expression of a truncated apo-E isoform, if any.”
Quote in the paperSubstantial claim - Interpretationreasoning
In the absence of secondary hyperlipidaemia, the finding argues in favour of facilitated FD precipitation in apo-e2/e3Groningen subjects because of grossly diminished clearance of the remaining apo-E2-containing lipoproteins.
“In the absence of secondary hyperlipidaemia, this ¢nding argues in favour of facilitated FD precipitation in apo-e 2 /e 3Groningen subjects because of the grossly diminished clearance of the remaining apo-E 2 containing lipoproteins.”
Quote in the paperSubstantial claim - Interpretationreasoning
The G-insertion is predicted to cause a frameshift.
“The mutation, designated apoe 3Groningen , was predicted to cause a frameshift, a premature stop codon at codon 146 (AAG-TAA) and the expression of a truncated apo-E protein, if any.”
Quote in the paperSubstantial claim - Interpretationown data
The electrophoresis pattern of subjects with apo-e2/e3Groningen showed the classical broad-beta band, indicative of FD.
“Their electrophoresis pattern showed the classical broad-beta band, indicative of FD.”
Quote in the paperSubstantial claim - Study design and conductown data
The mutant primer did not yield false-positive PCR products in 100 previously tested apo-E genotyping samples.
“In addition, the possibility of false-positive results caused by the mutant primer was tested in 100 previously tested samples of apo-E genotyping.None of these samples yielded a PCR product.”
Quote in the paperSubstantial claim
- May combine two claims. 8
- Classified as probably not a substantial claim. 1
May combine two claims.
Findingown dataAt age 49, the patient's serum cholesterol, triglycerides and HDL-cholesterol were 4.70, 8.31 and 1.17 mmol/L, respectively.
“At that time, serum cholesterol, triglycerides and high-density lipoprotein (HDL)-cholesterol were 4.70, 8.31 and 1.17 mmol/L, respectively.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningNeither the RFLP method nor the minisequencing method is able to detect the apo-e3Groningen allele.
“Neither of these two methods is able to detect the apoe 3Groningen allele and we therefore constructed a new allele-speci¢c PCR for its detection.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataSamples found positive in the family investigation were subjected to sequencing, which yielded the same results.
“The samples that were found positive in the family investigation were subjected to sequencing, which yielded the same results.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe minisequencing method was not affected by the G-insertion because it used different primers, resulting in assignment of the apo-e2/e3 genotype.
“The minisequencing method was not a¡ected because of the use of di¡erent primers, resulting in assignment of the apo-e 2 /e 3 genotype.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe RFLP method of Reymer et al. failed to amplify the apo-e3Groningen allele, resulting in amplification of only the apo-e2 allele and erroneous assignment of the apo-e2/e2 genotype in the proband.
“Since the apo-e 3Groningen allele was not ampli¢ed, the RFLP method of Reymer et al. 4 resulted in the mere ampli¢cation of the apo-e 2 allele and erroneous assignment of the apo-e 2 /e 2 genotype in the apo-e 2 / e 3Groningen proband.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataAbnormal serum lipids also occurred in relatives without the truncated apo-E, so this may also be caused by other familial lipid abnormalities.
“Since abnormal serum lipids also occurred in relatives without the truncated apo-E, this may also be caused by other familial lipid abnormalities.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn heterozygous subjects, described truncated apo-E mutations cause low to normal serum apo-E levels, in conjunction with normal or occasionally abnormal serum lipid indices.
“In heterozygous subjects, they cause low to normal serum apo-E levels, 9--11,14--16 in conjunction with normal 9,12--16 or occasionally abnormal serum lipid indices.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 9--11,14--16
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown dataThe small number of subjects with apo-e3Groningen limits statistical analysis, and firm conclusions cannot be drawn from this study.
“However, the small number of subjects with apo-e 3Groningen limits statistical analysis, and ¢rm conclusions cannot be drawn from this study.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAll described mutations lead in their homozygous forms to apo-E deficiency, elevated serum lipid indices and abnormally high VLDL-cholesterol/serum triglyceride ratios, the latter being indicative of FD.
“All of the described mutations lead in their homozygous forms to apo-E de¢ciency, 9--11,14--16 elevated serum lipid indices 9--11,14--16 and abnormally high VLDL-cholesterol/serum triglyceride ratios, 9--11,14,15 the latter being indicative for FD.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 9--11,14--16
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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?
Five APOE Groningen (Glu96fsTer50) carriers were detected in a family study, of which only three cases with the E2 allele, including the proband, exhibited type III HLP.
“Five APOE Groningen (Glu96fsTer50) carriers were detected in a family study, of which only three cases with the E2 allele, including the proband, exhibited type III HLP.”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [41]
APOE Groningen (Glu96fsTer50) was detected in the analysis of a type III HLP case.
“APOE Groningen (Glu96fsTer50) was detected in the analysis of a type III HLP case.”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [41]
APOE Groningen (Glu96fsTer50) was identified as a mutation in which a G was inserted in codon 95 or 96 of the APOE3 allele.
“APOE Groningen (Glu96fsTer50) was identified as a mutation in which a G was inserted in codon 95 or 96 (95AAG96GAG>95AAG96GGA-G) of the APOE3 allele41).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [41]
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Pek, S. L. T., Dissanayake, S., Chen, H. M., Tai, E. S., & Subramaniam, T. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.08.028
- Authors
- Dijck-Brouwer, D. A. J., van Doormaal, J. J., Kema, I. P., Brugman, A. M., Kingma, A. W., & Muskiet, F. A. J.
- Affiliations
- Pathology and Laboratory Medicine;
- University Medical Center Groningen (NL)
- Venue
- Annals of Clinical Biochemistry: International Journal of Laboratory Medicine
- Publisher
- SAGE Publications
- Published
- 2005-07-01
- Volume
- 42
- Issue
- 4
- Pages
- 264-268
- ISSN
- 0004-5632 (ISSN-L)
- 1758-1001
- OpenAlex
- W2094201096
- Semantic Scholar
- bd0fcde5aad62dcf113593230b12e815a73a4e89
- Cited by
- 9
- References
- 15
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of Clinical Biochemistry International Journal of Laboratory Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- 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 › Genomics and Rare Diseases
- Keywords
- apolipoprotein E, premature stop codon, frameshift mutation, familial dysbetalipoproteinemia, serum lipids, LDL cholesterol, triglycerides
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Apolipoproteins E, DNA Mutational Analysis, Female, Genotype, Humans, Hyperlipoproteinemia Type III, Male, Middle Aged, Pedigree, Polymorphism, Restriction Fragment Length, Polymerase Chain Reaction, Frameshift Mutation, Codon, Nonsense
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
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 ›
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