title: Three novel germ-line VHL mutations in Hungarian von Hippel-Lindau patients, including a nonsense mutation in a fifteen-year-old boy with renal cell carcinoma.
abstract: BACKGROUND
  Von Hippel-Lindau disease is an autosomal dominantly inherited highly penetrant tumor syndrome predisposing to retinal and central nervous system hemangioblastomas, renal cell carcinoma and phaeochromocytoma among other less frequent complications.
  
  
  METHODS
  Molecular genetic testing of the VHL gene was performed in five unrelated families affetced with type I VHL disease, including seven patients and their available family members.
  
  
  RESULTS
  Molecular genetic investigations detected three novel (c.163 G > T, c.232A > T and c.555C > A causing p.Glu55X, p.Asn78Tyr and p.Tyr185X protein changes, respectively) and two previously described (c.340 + 1 G > A and c.583C > T, resulting in p.Gly114AspfsX6 and p.195GlnX protein changes, respectively) germline point mutations in the VHL gene. Molecular modeling of the VHL-ElonginC-HIF-1alpha complex predicted that the p.Asn78Tyr amino acid exchange remarkably alters the 77-83 loop structure of VHL protein and destabilizes the VHL-HIF-1alpha complex suggesting that the mutation causes type I phenotype and has high risk to associate to renal cell carcinoma. The novel p.55X nonsense mutation associated to bilateral RCC and retinal angioma in a 15-year-old male patient.
  
  
  CONCLUSIONS
  We describe the earliest onset renal cell carcinoma in VHL disease reported so far in a 15-year-old boy with a nonsense VHL mutation. Individual tailoring of screening schedule based on molecular genetic status should be considered in order to diagnose serious complications as early as possible. Our observations add to the understanding of genotype-phenotype correlation in VHL disease and can be useful for genetic counseling and follow-up of VHL patients.
authors.affiliation: Department of Ophthalmology, University of Debrecen, Medical and Health Science Center, 98. Nagyerdei bld, 4012, Debrecen, Hungary. losigeri@gmail.com
authors.forename: Gergely
authors.initials: G
authors.lastname: Losonczy
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fazakas
authors.forename: György
authors.initials: G
authors.lastname: Pfliegler
authors.forename: István
authors.initials: I
authors.lastname: Komáromi
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Balázs
authors.forename: Krisztina
authors.initials: K
authors.lastname: Pénzes
authors.forename: András
authors.initials: A
authors.lastname: Berta
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense; D017931:DNA Primers; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human