title: The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).
abstract: Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations.
authors: Division of Neonatology, University Hospital Merkur, Zagreb, Croatia.
authors: Nikica Ljubas
authors: NL
authors: Tomasic
authors: Lucie
authors: L
authors: Piterkova
authors: Chad
authors: C
authors: Huff
authors: Ernest
authors: E
authors: Bilic
authors: Donghoon
authors: D
authors: Yoon
authors: Galina Y
authors: GY
authors: Miasnikova
authors: Adelina I
authors: AI
authors: Sergueeva
authors: Xiaomei
authors: X
authors: Niu
authors: Sergei
authors: S
authors: Nekhai
authors: Victor
authors: V
authors: Gordeuk
authors: Josef T
authors: JT
authors: Prchal
mesh_terms: D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D017523:Croatia; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000097:blood / Q000494:pharmacology; D005192:Family Health; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005838:Genotype; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011086:Polycythemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012426:Russia; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
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