Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors

Gordeuk, Victor R.; Sergueeva, Adelina; Miasnikova, Galina Y.; Okhotin, Daniel J.; Voloshin, Yaroslav; Choyke, Peter L.; Butman, John A.; Jedlickova, Katerina; Prchal, Josef T.; Polyakova, Lydia A.

doi:10.1182/blood-2003-07-2535

Cited by 248 publications

(252 citation statements)

References 40 publications

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“…A larger number of cases have been reported for the slightly less specific genetic disorder of Chuvash Polycythemia, where homozygosity for hypomorphic alleles for VHL results in elevated levels of both HIF1α and EPAS1/HIF2α (41). The phenotype for Chuvash Polycythemia appears very similar to that for the specific EPAS1 gain of function mutations, with excessive erythrocytosis, an excess risk of thrombotic events at a young age, and pulmonary hypertension (42)(43)(44)(45). In both conditions, the excessive erythrocytosis is generally managed by venesection in the belief that this may reduce the incidence of thrombotic events.…”

Section: Discussionmentioning

confidence: 97%

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Beall

Cavalleri

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

730

770

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By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor

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Section: Discussionmentioning

confidence: 97%

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Beall

Cavalleri

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

730

770

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“…Congenital polycythemia patients manifest increased red blood cell counts, increased frequency of vertebral hemangiomas, varicose veins, and elevated serum VEGF concentrations, as well as premature mortality related to cerebrovascular events and peripheral thrombosis, but do not otherwise develop VHL-associated tumors. The opposite is not true; VHL patients do occasionally develop polycythemias [Gordeuk et al, 2004]. It is probable that VHL dosage is important in determining cell fate.…”

Section: Introductionmentioning

confidence: 82%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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“…9,10 The best characterized of these mutations is the c.598C4T (Arg200Trp) mutation which is found in a patients with Chuvash polycythaemia and is thought to have arisen as a founder effect 14 000-62 000 years ago. 66 Patients with Chuvash polycythaemia homozygous for a VHL 598C4T mutation are reported to have polycythaemia, vertebral haemangiomas, pulmonary hypertension, varicose veins and elevated serum VEGF concentrations, but, apparently not an increased risk of spinocerebellar haemangioblastomas, RCC or phaeochromocytoma.…”

Section: Function Of the Vhl Tumour Suppressor Genementioning

confidence: 99%

“…66 Patients with Chuvash polycythaemia homozygous for a VHL 598C4T mutation are reported to have polycythaemia, vertebral haemangiomas, pulmonary hypertension, varicose veins and elevated serum VEGF concentrations, but, apparently not an increased risk of spinocerebellar haemangioblastomas, RCC or phaeochromocytoma. 10 In addition to the phenotypic variability associated with allelic heterogeneity, genetic modifiers may influence the phenotypic expression of VHL disease. Thus Webster et al 67 reported that patients with retinal angiomas had a higher risk of cerebellar haemangioblastoma and RCC than those without retinal involvement.…”

Section: Function Of the Vhl Tumour Suppressor Genementioning

confidence: 99%

“…In addition germline VHL gene mutations may be detected in patients with autosomal dominant familial non-syndromic phaeochromocytoma 7,8 and specific VHL missense mutations can cause an autosomal recessive form of polycythaemia without any evidence of VHL disease. 9,10 Prior to the advent of molecular genetic testing VHL disease was estimated to have an incidence of 1/36 000 live births in Eastern England and prevalences of 1/39 000 in South-West Germany and 1/53 000 in Eastern England. 11,12 VHL disease is suggested to account for approximately a third of patients with a CNS haemangioblastoma, 450% of patients with a retinal angioma, 1% of patients with RCC, 50% of patients with apparently isolated familial phaeochromocytoma and 11% of patients with an apparently sporadic phaeochromocytoma 5,8,13 (and unpub- Haemangioblastomas with an associated cyst tend to become symptomatic sooner.…”

Section: Introductionmentioning

confidence: 99%

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