title: Novel Homozygous Mutation of the Internal Translation Initiation Start Site of VHL is Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms.
abstract: Congenital secondary erythrocytosis is a rare disorder characterized by increased red blood cell production. An important cause involves defects in the oxygen sensing pathway, in particular the PHD2-VHL-HIF axis. Mutations in VHL are also associated with the von Hippel-Lindau tumor predisposition syndrome. The differences in phenotypic expression of VHL mutations are poorly understood. We report on three patients with erythrocytosis, from two unrelated families. All patients show exceptionally high erythropoietin (EPO) levels, and are homozygous for a novel missense mutation in VHL: c.162G>C p.(Met54Ile). The c.162G>C mutation is the most upstream homozygous VHL mutation described so far in patients with erythrocytosis. It abolishes the internal translational start codon, which directs expression of VHLp19, resulting in the production of only VHLp30. The exceptionally high EPO levels and the absence of VHL-associated tumors in the patients suggest that VHLp19 has a role for regulating EPO levels that VHLp30 does not have, whereas VHLp30 is really the tumor suppressor isoform.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Bartels
authors.affiliation: Department of Pediatric Hematology/Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marieke M
authors.initials: MM
authors.lastname: van der Zalm
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Brigitte A
authors.initials: BA
authors.lastname: van Oirschot
authors.affiliation: Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marieke J H A
authors.initials: MJ
authors.lastname: Kruip
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jerney J J M
authors.initials: JJ
authors.lastname: Gitz-Francois
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Van Solinge
authors.affiliation: Department of Pediatric Hematology/Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Bierings
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Wijk
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D002675:Child, Preschool; D018387:Codon, Initiator; D004909:Erythrocyte Indices; D004921:Erythropoietin / Q000097:blood; D005260:Female; D023061:Gene Order; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010442:Peptide Chain Initiation, Translational / Q000235:genetics*; D011086:Polycythemia / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018387:Codon, Initiator; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: VHL; congenital erythrocytosis; erythropoietin; oxygen sensing; von Hippel-Lindau tumor suppressor