title: Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.
abstract: Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.
authors.affiliation: Division of Hematology, University of Utah and VA Health Care, Salt Lake City, UT 84132, USA.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lanikova
authors.forename: Felipe
authors.initials: F
authors.lastname: Lorenzo
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Hari
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Richard
authors.initials: R
authors.lastname: Drachtman
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000293:Adolescent; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000235:genetics; D011086:Polycythemia / Q000151:congenital / Q000235:genetics*; D017433:Protein Structure, Secondary; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
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