Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry

Abstract

This mutation has a wider geographic distribution than originally presumed and haplotype analysis suggests a common origin of the Arg200Trp mutation in the 4 families, but it still remains to be established if it has arisen independently of the Chuvash population. (

A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove

“…The EpoR, 3 VHL, [8][9][10] and PHD2 16 genes, as reflected in the current OMIM classification of erythrocytosis, were screened in all patients with IE. Consequently, a novel mutation, G1112A, in PHD2 exon 3 ( Figure 1A) was detected in 1 patient with wild-type EpoR and VHL.…”

“…The mutation also exists in families of Asian and European ancestry. [8][9][10][11][12] The VHL protein is part of an E3 ubiquitin ligase complex that targets hypoxia inducible transcription factor-␣ (HIF-␣) for proteasomal degradation. This is dependent on hydroxylation of specific proline residues in the oxygen-dependent degradation domain (ODD) of HIF-␣ mediated by the prolyl hydroxylase domain (PHD; also known as HPH and EGLN) family of prolyl hydroxylases.…”

The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels

“…We used a previously developed registry of IE cases 12,16,17 to assess the frequency of JAK2 exon 12 mutations, and to determine the clinicopathologic features associated with these mutations. Of the 181 cases currently included in the IE registry, 14 had identified defects in the EPOR, VHL, or PHD2 genes ( Figure 1); none of the patients was positive for the V617F JAK2 mutation (data not shown).…”

“…16 Cases entered into the registry were those with a raised red cell mass in the absence of hyperplasia of other cell lineages which was not the result of various identifiable secondary causes, and which did not fulfill the diagnostic criteria for PV proposed by the British Committee for Standards in Haematology (BCSH). 19 A comparison between these criteria with those proposed by the World Health Organization 20 is provided in Table 1.…”

“…The von Hippel Lindau (VHL) and prolyl hydroxylase domain 2 (PHD2) proteins are both involved in the proteasomal degradation of HIF, preventing transcription of HIF target genes such as EPO. Loss-of-function mutations have been described in the VHL [14][15][16] and PHD2 17 proteins in individuals with erythrocytosis and dysregulated Epo production.…”