title: Von Hippel-Lindau gene deletion and expression of hypoxia-inducible factor and ubiquitin in optic nerve hemangioma.
abstract: OBJECTIVE
  Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome expressed in multiple organs caused by germline alterations of the VHL gene. We have shown VHL deletion in the "stromal" cells of retinal angiomas. The VHL protein-associated complex is a primary ubiquitin ligase for the ubiquitination of hypoxia-inducible factor (HIF). This study examines VHL and ubiquitin expression in optic nerve hemangiomas and juxtapapillary angiomas.
  
  
  METHODS
  Using microdissection and polymerase chain reaction, four optic nerve hemangiomas (one also had juxtapapillary angioma) associated with VHL disease were analyzed for loss of heterozygosity in the VHL gene. In addition, expression of HIF and ubiquitin was evaluated in these tumors by immunohistochemistry.
  
  
  RESULTS
  All informative optic nerve and juxtapapillary lesions showed loss of heterozygosity in the VHL gene detected in vacuolated "stromal" cells. Both HIF and ubiquitin were highly expressed in the hemangiomas of all four VHL cases.
  
  
  CONCLUSIONS
  Like retinal angiomas and other VHL tumor lesions, VHL gene deletion is found in optic nerve hemangiomas and juxtapapillary angiomas. These tumor cells also express HIF and ubiquitin, the protein responsible for the negative regulation of HIF that results in the hypervascularization characteristic of VHL disease.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Youn-Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Joseph
authors.initials: J
authors.lastname: Hackett
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006391:Hemangioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D009898:Optic Disk; D019574:Optic Nerve Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human