CoChat
Sign Up
Cited by 8Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene

Open access
Leren, Trond P., Strøm, Thea Bismo, Berge, Knut Erik·2016·Molecular Genetics and Metabolism Reports
DOI 10.1016/j.ymgmr.2016.10.007PMC PMC5094269
Open this paper in CoChat — free accountOpen PDF

Abstract

Subjects with hypercholesterolemia who do not carry a mutation in the low density lipoprotein receptor gene, in the apolipoprotein B gene or in the proprotein convertase subtilisin/kexin type 9 gene, could possible carry a mutation in the apolipoprotein E (APOE) gene. DNA from 844 unrelated hypercholesterolemic subjects who did not carry a mutation in any of the three above mentioned genes, was subjected to DNA sequencing of the APOE gene. Two subjects were found to be heterozygous for mutation p.Thr5*. This mutation which generates a stop codon in the signal peptide, is assumed to prevent the synthesis of APOE. Family studies revealed that the mutation was carried on an APOE4 allele in both families. In one of the families only those who had an APOE2 allele as the second allele, had hypercholesterolemia. These were functionally hemizygous for APOE2 and presented with a Type III hyperlipoproteinemia phenotype. However, in the second family, hypercholesterolemia was observed in the index patient who had APOE3 as the second allele, but not in four heterozygous family members who also had APOE3 as the second allele. These findings underscore that the phenotypic expression of mutations in the APOE gene is variable and that the trait exhibits reduced penetrance.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.ymgmr.2016.10.007

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • In one family, only two of the five carriers of the APOE2 allele showed type III HLP.

    “In one family, only two of the five carriers of the APOE2 allele showed type III HLP.”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [39]

    In Results and discussion (Family T0657), the five people are carriers of the p.Thr5* mutation, not five carriers of an APOE2 allele. Only two had an APOE2 allele, and both showed a Type III hyperlipoproteinemia phenotype; the other three were APOE4 homozygotes. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In the second family, the five carriers did not have the APOE2 allele and did not have type III HLP.

    “Meanwhile, in the second family, the five carriers did not have the APOE2 allele and did not have type III HLP.”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [39]

    In Results and discussion (Family T0544; page unavailable), the paper identifies the index patient and four other carriers as APOE3/4 heterozygotes, so those five did not have an APOE2 allele. It reports Type III hyperlipoproteinemia in the other family, not among these five. However, it says seven family members carried the mutation in the second family, so five was not the total number of carriers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • APOE (p.Thr5*) does not express apoE because the fifth position of the signal peptide is a stop codon.

    “APOE (p.Thr5*) does not express apoE because the fifth position of the signal peptide is a stop codon.”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [39]

    The Results and discussion section (‘Identification of mutation p.Thr5*’; page unavailable) says codon 5 is in the signal peptide and that the mutation is expected to prevent APOE synthesis. The claim states this predicted effect as a certainty. The paper also reports measurable serum apoE in heterozygous carriers, so ‘does not express apoE’ should not be read as saying carriers have no apoE at all. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Heterozygous APOE (p.Thr5*) was found in two families in a screening of a hypercholesterolemic, hypertriglyceridemic population in Norway.

    “Heterozygous APOE (p.Thr5*) was found in two families in a screening of a hypercholesterolemic, hypertriglyceridemic population in Norway39).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [39]

    The Results and discussion (Identification of mutation p.Thr5*) report that screening 844 hypercholesterolemic subjects found two p.Thr5* heterozygotes from two families; both also had hypertriglyceridemia. The Materials and methods (Subjects) describe the screened group as referred for hypercholesterolemia testing, not as a population selected for both conditions. The paper places the families in southern Norway. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 19

  1. [1]Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The metabolic & molecular basis of inherited disease 2001 McGraw-Hill New York 2863 2914
  2. [2]Soutar A.K. Rare genetic causes of autosomal dominant or recessive hypercholesterolemia IUBMB Life 62 2010 125 131 20073037
  3. [3]Patel R.S. Scopelliti E.M. Savelloni J. Therapeutic management of familial hypercholesterolemia: current and emerging drug therapies Pharmacotherapy 35 2015 1189 1203 26684558
  4. [4]Futema M. Whittall R.A. Kiley A. Cooper J.A. Badmus E. Leigh S. Karpe F. Neil H.A. Simon Broome Register Group Humphries S.E. Analysis of the frequency and spectrum of mutations recognized to cause familial hypercholesterolemia in routine clinical practice in a UK specialist hospital clinic Atherosclerosis 229 2013 161 168 23669246 PMC3701838
  5. [6]Cenarro A. Etxebarria A. de Castro-Oros I. Stef M. Bea A.M. Palacios L. Mateo-Gallego R. Benito-Vicente A. Ostolaza H. Tejedor T. Martin C. Civeira F. The p.Leu167del mutation in APOE gene causes autosomal dominant hypercholesterolemia by down-regulation of LDL receptor expression in hepatocytes J. Clin. Endocrinol. Metab. 101 2016 2113 2121 27014949
  6. [7]Awan Z. Choi H.Y. Stitziel N. Ruel I. Bamimore M.A. Husa R. Gagnon M.H. Wang R.H. Peloso G.M. Hegele R.A. Seidah N.G. Kathiresan S. Genest J. APOE p.Leu167del mutation in familial hypercholesterolemia Atherosclerosis 231 2013 218 222 24267230
  7. [8]Wintjens R. Dominique B. Belabbas K. MBou F. Girardet J.P. Tounian P. Jolly M. Boccara F. Cohen A. Karsenty A. Dubern B. Carel J.C. Azar-Kolakez A. Feillet F. Labarthe F. Gorsky A.M.C. Horovitz A. Tamarindi C. Kieffer P. Lienhardt A. Lascols O. Di Filippo M. Dufernez F. J. Lipid Res. 57 2016 482 491 26802169 PMC4766997
  8. [9]Mahley R.W. Rall S.C. Type III hyperlipoproteinemia (dysbetalipoproteinemia), The role of apolipoprotein E in normal and abnormal lipoprotein metabolism Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic & Molecular Basis of Inherited Disease 2001 McGraw-Hill New York 1953 1980
  9. [10]Das H.K. McPherson J. Bruns G.A.P. Karathanasis S.K. Breslow J.L. Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene J. Biol. Chem. 260 1985 6240 6247 3922972
  10. [11]Paik Y.K. Chang D.J. Reardon C.A. Davis G.E. Mahley R.W. Taylor J.M. Nucleotide sequence and structure of the human apolipoprotein E gene Proc. Natl. Acad. Sci. U. S. A. 325 1985 3445 3449 PMC397792 2987927
  11. [12]Weisgraber K.H. Innerarity T.L. Mahley R.W. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site J. Biol. Chem. 257 1982 2518 2521 6277903
  12. [13]Friedewald W.T. Levy R.I. Fredrickson D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge Clin. Chem. 18 1972 499 502 4337382
  13. [14]Feussner G. Feussner V. Hoffmann M.M. Lohrmann J. Wieland H. März W. Molecular basis of Type III hyperlipoproteinemia in Germany Hum. Mutat. 11 1998 417 423 9603433
  14. [16]Rolleri M. Vivona N. Emmanuele G. Cefalu A.B. Pisciotta L. Guido V. Noto D. Fiore B. Barbagallo C.M. Notarbartolo A. Travali S. Bertolini S. Averna M.R. Two Italian kindreds carrying the Arg135 ➔ Ser mutation of the ApoE gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele Nutr. Metab. Cardiovasc. Dis. 13 2003 93 99 12929622
  15. [17]Visser M.E. Dallinga-Thie G.M. Pinto-Sietsma S.J. Defesche J.C. Stroes E.S. van der Valk P.R. APOE1 mutation in a patient with type III hyperlipoproteinemia: detailed genetic analysis required Neth. J. Med. 70 2012 278 280 22859420
  16. [18]Feussner G. Dobmeyer J. Gröne H.J. Lohmer S. Wohlfeil S. A 10-bp deletion in the apolipoprotein ԑ gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia Am. J. Hum. Genet. 58 1996 281 291 8571954 PMC1914549
  17. [19]de Villiers W.J.S. van der Westhuysen D.R. Coetzee G.A. Henderson H.E. Marais A.D. The apolipoprotein E2(Arg154Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance Arterioscler. Thromb. Vasc. Biol. 17 1997 865 872 9157949
  18. [20]Ghiselli G. Schaefer E.J. Gascon P. Brewer H.B. Type III hyperlipoproteinemia associated with apolipoprotein E deficiency Science 214 1981 1239 1241 6795720
  19. [21]Rasmussen K.L. Tybjærg-Hansen A. Nordestgaard B.G. Frikke-Schmidt R. Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease Data Brief 6 2016 923 932 26937471 PMC4753393

Cited by

Sorted by citations

Authors
Leren, T. P., Strøm, T. B., & Berge, K. E.
Affiliations
Oslo University Hospital (NO)
Corresponding author
Leren, Trond P.
ORCID
Venue
Molecular Genetics and Metabolism Reports
Publisher
Elsevier BV
Published
2016-12
Volume
9
Pages
67-70
ISSN
2214-4269 (ISSN-L)
DOI
10.1016/j.ymgmr.2016.10.007
PMC
PMC5094269
OpenAlex
W2545570364
Cited by
8
References
2
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Genetics and Metabolism Reports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
APOE gene, hypercholesterolemia, APOE ε4, ApoE2 allele, type III hyperlipoproteinemia, incomplete penetrance, familial hypercholesterolemia

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