Abstract
BackgroundVon 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.MethodsMolecular 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.ResultsMolecular 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.ConclusionWe 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.
Highlights
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
No alterations could be detected in the Von Hippel-Lindau (VHL) gene with the Multiplex Ligation-dependent Probe Amplification (MLPA) test
A recent computational study could not confirm the dose-dependent effect of VHL-HIF1alpha dissociation and suggests that the canonical configuration of the wild-type beta domain is vital for the efficient functioning of the complex and that mutation of any of the residues implicated in the H-bond network in the binding site disrupts HIF binding [32]
Summary
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. Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited highly penetrant tumor syndrome affecting 1 in 36,000 individuals worldwide. VHL disease predisposes to retinal and central nervous system hemangioblastomas (HB), renal cell carcinoma (RCC), phaeochromocytoma, pancreatic endocrine tumors, endolymphatic functions as the substrate recognition component of an E3ubiquitin ligase that ubiquitinates HIF-1aplha under normoxic conditions resulting in HIF-1alpha proteolysis [3]. Two important binding sites within VHL protein have been identified; one responsible for elongin C binding in the alpha domain (amino acid residues 157– 170) and the other in the beta domain responsible for the binding of HIF1alpha (amino acid residues 91–113) [4]. We describe 7 members of 5 families with three novel and one previously reported point mutations in the VHL gene and correlate genetic findings with clinical phenotype
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