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Chuvash polycythemia is an autosomal recessive erythrocytosis characterized by elevated hemoglobin and erythropoietin levels due to dysregulated hypoxia signaling. This condition results from germline loss-of-function variants in the von Hippel-Lindau gene (Gene Symbol), leading to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and consequent upregulation of erythropoietic targets. Clinically, Chuvash polycythemia presents with increased red cell mass, low-to-normal oxygen saturation, and thrombotic risk in the absence of VHL-associated tumors (Disease Name).
Genetic evidence demonstrates that the c.598C>T (p.Arg200Trp) variant is homozygous in all affected individuals in initial cohorts, including 61 Chuvash probands and multiple non-Chuvash homozygotes, and is absent in unaffected homozygous carriers (PMID:12415268). Segregation within five multiplex families confirms recessive inheritance with complete penetrance among homozygotes and asymptomatic heterozygous carriers (PMID:11987242). Compound heterozygotes combining c.598C>T and other VHL missense variants (e.g., c.562C>G) have also been identified in seven additional probands, underscoring allelic heterogeneity (PMID:12844285).
Beyond p.Arg200Trp, a spectrum of VHL variants associates with Chuvash polycythemia, including c.562C>G (p.Leu188Val), c.413C>T (p.Pro138Leu), and deep intronic splice-altering mutations within a cryptic exon (e.g., c.340+761T>C) identified in seven families, which modulate VHL transcript and protein levels (PMID:29891534). A founder effect for c.598C>T is supported by haplotype analysis of 101 mutation-bearing subjects and 447 controls, indicating a single ancestral event (PMID:14604959).
Functional studies reveal that p.Arg200Trp impairs binding of pVHL to hydroxylated HIF1α, attenuating prolyl-hydroxylation–dependent ubiquitination and proteasomal degradation of HIF1α, thereby sustaining hypoxic gene expression in normoxia (PMID:12415268). Transcriptomic analyses of cis double VHL mutants correlate graded pVHL dysfunction with phenotypic severity, validating the continuum model of tumor suppression (PMID:25371412). Splicing defects in a newly described exon E1′ further demonstrate that altered VHL expression levels finely tune erythroid sensitivity to erythropoietin.
No studies have reported heterozygous carriers developing Chuvash polycythemia or increased tumor risk under homozygous conditions, arguing against dominant-negative effects or tumorigenesis in CP families. Conversely, distinct VHL alleles outside the C-terminal domain predispose to classic VHL syndrome, confirming genotype–phenotype specificity.
In summary, autosomal recessive VHL variants—chiefly c.598C>T (p.Arg200Trp)—cause Chuvash polycythemia by disrupting pVHL-mediated HIF1α turnover. Genetic screening for c.598C>T provides a rapid, cost-effective diagnostic tool in endemic regions, and mechanistic insights into VHL dosage sensitivity inform therapeutic targeting of hypoxia pathways.
Key Take-home: Biallelic VHL loss-of-function, especially c.598C>T (p.Arg200Trp), definitively causes Chuvash polycythemia through impaired HIF1α degradation, supporting targeted genetic diagnostics and pathway-based interventions.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongHomozygous c.598C>T in >61 probands; segregation in 5 multiplex families; compound heterozygotes in 7 additional cases Functional EvidenceStrongImpaired pVHL–HIF1α binding and ubiquitination in vitro; graded dysfunction correlates with clinical severity |