CoChat
Sign Up
Cited by 106Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismEar and Head Tumors

Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia

Open access
Pastore, Yves, Jedlickova, Katerina, Guan, Yongli, Liu, Enli, Fahner, James, Hasle, Henrik, Prchal, Jaroslav F., Prchal, Josef T.·2003·The American Journal of Human Genetics
DOI 10.1086/377108PMC PMC1180379
Open this paper in CoChat — free account

Abstract

The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO). The autosomal dominant cancer-predisposition von Hippel-Lindau (VHL) syndrome is due to inheritance of a single mutated allele of VHL. In contrast, we recently showed that homozygous germline 598C-->T VHL mutation leads to Chuvash polycythemia (CP). We subsequently found VHL mutations in three unrelated individuals unaffected with CP, one of whom was compound heterozygous for the 598C-->T mutation and another VHL mutation. We now report seven additional polycythemic patients with VHL mutations in both alleles. Two Danish siblings and another American boy were homozygous for the VHL 598C-->T mutation. Three unrelated white Americans were compound heterozygotes for 598C-->T and another VHL mutation, 562C-->G in two and 574C-->T in the third. Additionally, a Croatian boy was homozygous for a 571C-->G VHL mutation, the first example of homozygous VHL germline mutation causing polycythemia, other than the VHL 598C-->T mutation. We have not observed VHL syndrome-associated tumors in polycythemic subjects or their heterozygous relatives; however, this will need to be evaluated by longitudinal studies. Over all, we found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo we have examined have mutations of both VHL alleles. Those findings, along with reports of CP, underscore that VHL mutations are the most frequent cause of congenital polycythemia and define a new class of polycythemic disorder, polycythemias due to augmented hypoxia sensing.

Integrity signals

Registry

Crossref · 10.1086/377108

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J. F., & Prchal, J. T.
Affiliations
  • Baylor College of Medicine (US)
  • Helen DeVos Children's Hospital (US)
  • Regionshospitalet Viborg (DK)
Corresponding author
Prchal, Josef T.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2003-08
Volume
73
Issue
2
Pages
412-419
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/377108
PMC
PMC1180379
OpenAlex
W2035717068
Cited by
106
References
31
Citations by year
2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 6 · 2012: 3
FWCI
4.46
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL5007-08, Z01HL005007, R01HL066333, R01HL66333-01)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Ear and Head Tumors
Keywords
von Hippel-Lindau gene, VHL mutation, Chuvash polycythemia, hypoxia sensing, HIF-1α, erythropoietin, compound heterozygosity, hypoxia-inducible factor
MeSH terms
Adolescent, Adult, Alleles, Hypoxia, Base Sequence, Child, DNA, DNA Mutational Analysis, Female, Heterozygote, Homozygote, Humans, Ligases, Male, Models, Molecular, Mutation, Pedigree, Polycythemia, Transcription Factors, Genes, Tumor Suppressor, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Macromolecular Substances, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit

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