Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia

@article{Ang2002DisruptionOO,
  title={Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia},
  author={Sonny O. Ang and Hua Chen and Kiichi Hirota and Victor R. Gordeuk and Jaroslav Jelinek and Yongli Guan and Enli Liu and Adelina I. Sergueeva and Galina Y. Miasnikova and David R. Mole and Patrick H. Maxwell and David W. Stockton and Gregg L. Semenza and Josef T. Prchal},
  journal={Nature Genetics},
  year={2002},
  volume={32},
  pages={614-621}
}
Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel–Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C→T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein… 
Mutations in the VHL gene in sporadic apparently congenital polycythemia.
TLDR
It is proposed that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration, and evaluated the role of VHL in 8 children with a history ofpolycythemia and an elevated serum EpO level.
Chuvash polycythemia: diagnosis and management.
  • V. Gordeuk
  • Medicine
    Clinical advances in hematology & oncology : H&O
  • 2011
TLDR
Researchers have shown that the condition is caused by a specific mutation in the VHL gene that results in an R200W amino acid substitution, which results in increased concentrations of erythropoietin, the hormone that promotes production of red blood cells, which causes polycythemia (or erythrocytosis).
Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression.
TLDR
Up-regulation of the hypoxic response leads to decreased expression of hepcidin that may be independent of increased erythropoietin levels and increased RBC counts.
Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia.
TLDR
It is found that up to half of the consecutive patients with apparent congenital polycythemia and increased serum Epo the authors have examined have mutations of both VHL alleles, underscore that VHL mutations are the most frequent cause of congenitalpolycythemias and define a new class of polycythemic disorder, polycymsias due to augmented hypoxia sensing.
Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.
TLDR
Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.
Two new mutations in the HIF2A gene associated with erythrocytosis
TLDR
Two new heterozygous HIF2A missense mutations are identified, M535T, and F540L, both associated with erythrocytosis, and evidence is presented here that this mutation impairs interaction of HIF‐2α with both VHL and PHD2.
Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.
TLDR
This work has identified the first large cluster of Chuvash erythrocytosis outside ChUVashia, which suggests that this familial polycythemia might be endemic in other regions of the world.
von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis.
TLDR
It is suggested that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice.
Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range
TLDR
The identification of two cases of familial erythrocytosis associated with heterozygous HIF2A missense mutations, namely Ile533Val and Gly537Arg, suggest the novel proposal that polycythemia observed in subjects with Hif2A mutations might also be due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels.
Erythrocytosis associated with a novel missense mutation in the HIF2A gene
TLDR
A new erythrocytosis-associated mutation is reported, p.Asp539Glu, in the HIF2A gene that compromises binding of HIF-2α to both PHD2 and VHL, and it is proposed that this mutation is the cause of ery throat cancer in this individual.
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