engleski

The phenotyphe of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvas polycytemia (VHL598C>T:R200W)

Mutations of the tumor-suppressor gene, VHL, a negative regulator of HIFs, have position- dependent distinct phenotypes including various tumors and polycythemia. Only two known homozygous VHL mutations cause polycythemia: an R200W mutation endemic in Chuvashia, Russia causing the first recognized disorder of augmented hypoxia sensing in normoxia and an H191D mutation in a Croatian boy. We report another polycythemic Croatian H191D homozygote, distantly related to the first H191D subject. Three generations were genotyped (23 relatives in both families). The VHL H191D mutation did not segregate among related subjects suggesting a high prevalence of heterozygosity in Croatians, but the haplotype analysis rather pointed to a common ancestor ~6 generations ago as the founder of this mutation. A recent report suggested that polycythemia in VHL R200W and H191D homozygotes is due to loss of JAK2 regulation via increased affinity of VHL R200W and H191D to SOCS1 which results in hypersensitivity of erythroid progenitors to erythropoietin. However, native homozygous VHL H191D erythroid progenitors, unlike those with the Chuvash R200W genotype, were not hypersensitive to erythropoietin. Our study further defines the hematologic phenotype of VHL H191D and provides additional evidence for unexplained phenotypic heterogeneity associated with the positional effect of VHL mutations.

polycythemia; mutation

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