Endemic Polycythemia in Russia: Mutation in the VHL Gene

Ang, Sonny; Chen, Hua; Gordeuk, Victor R.; Sergueeva, Adelina; Polyakova, Lydia A.; Miasnikova, Galina Y.; Královics, Róbert; Stockton, David W.; Prchal, Josef T.

doi:10.1006/bcmd.2002.0488

Cited by 126 publications

(95 citation statements)

References 12 publications

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“…Evidence from specific VHL disease-causing mutations which predispose to distinct patterns of tumor development (VHL disease subtypes 2A, 2B, 2C, and Chuvash Polycythemia -each of which carries a high risk for developing pheochromocytoma and greater or lesser penetrance for the hemangioblastoma and RCC phenotypes of the disease) suggests that the degree of HIF2α stabilization contributes substantially to the risk of RCC (Table 1) [40*]. Additionally, increasing evidence suggests that the dosage of HIF factors may influence the disease predisposition as evidenced by individuals who carry a very subtle alteration in the carboxyterminus of the VHL gene are predisposed to the autosomal recessive development of congenital polycythemia induced as a result of a small but not insignificant increase in HIF levels and a steady elevation of serum erythropoietin [41][42][43][44][45]. This prediction is further born out in an animal model of Chuvash polycythemia in which a homozygous mutation in the murine VHL allele confers a limited degree of HIF stabilization and elevated erythropoietin levels with concordant elevations in measured hematocrits in these animals [46].…”

Section: Hif-related Effects Of Vhl Lossmentioning

confidence: 99%

VHLinactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment

Rathmell¹,

Chen²

2008

Expert Review of Anticancer Therapy

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Clear cell renal cell carcinoma (ccRCC) provides a tumor paradigm for the integration of genetics, molecular biology, therapeutic target validation, and the introduction of high impact treatment strategies. Most cases of sporadic as well as familial ccRCC acquire somatic inactivating mutations of the von Hippel-Lindau tumor suppressor gene, VHL. pVHL, VHL gene product and a protein member of the E3 ubiquitin ligase family, acts in normal cells to direct the degradation and clearance of the hypoxia inducible factor (HIFα) transcription factor family, such that in its absence, as in ccRCC, the HIF proteins stabilize, accumulate to supraphysiologic levels, and activate the transcription of genes such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), which contributes substantially to the physiology of the tumor, and has been assessed indirectly as a prognostic factor. Molecularly targeted therapy blocking components of this pathway has been successfully introduced to the clinic with a substantive impact on clinical parameters of RCC. This review will examine the regulation of these molecular pathways in RCC and discuss the impact on the clinical management of patients with RCC.

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Section: Hif-related Effects Of Vhl Lossmentioning

confidence: 99%

VHLinactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment

Rathmell¹,

Chen²

2008

Expert Review of Anticancer Therapy

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“…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.…”

mentioning

confidence: 99%

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

Percy¹,

Scott²,

Erber³

et al. 2007

Haematologica

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“…[1][2][3][4] (ii) ECYT2: VHL, most frequently C598T/R200W, either as an isolated C598T mutation or in combination with other VHL mutations (C235T, G311T, G376T, G388C, A523G, C562G, C571G and C574T) or isolated VHL mutations other than C598T. [1][2][3][5][6][7] (iii) ECYT3: EGLN1 C950G/P317R, G1112A/R371H and A1121G/ H374R. [1][2][3] (iv) ECYT4: EPAS1 A1603G/M535V, G1605A/M535I, G1609A/ G537R, G1609T/G537Y and C1617G/D539Q.…”

Section: Omim# Of the Diseasementioning

confidence: 99%

“…5 (ii) Ischia polycythemia (island of Ischia, Bay of Naples, Italy). 6 The exact prevalence for Chuvash polycythemia and Ischia polycythemia is not known, but likely o1:100 000.…”

Section: Estimated Frequency Of the Diseasementioning

confidence: 99%