title: Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype.
abstract: OBJECTIVE
  von Hippel-Lindau (VHL) disease is a dominantly inherited, multisystemic tumor syndrome caused by mutations in the VHL gene. This study was conducted to establish genotype-phenotype correlations between the positions of disease-causing missense mutations and the ocular phenotypes of VHL disease.
  
  
  METHODS
  Participants with clinically defined VHL disease and documented germline missense mutations in the VHL gene were identified in a cross-sectional study (n=412). Statistical analysis was used to correlate the position of the missense mutation in either the alpha- or beta-domain of the VHL protein with the ocular disease phenotype.
  
  
  RESULTS
  Missense mutations among study participants were located in 47 of the 213 possible codons in the VHL gene. Almost all mutations (98.5%) were located in one of two structural domains of the VHL protein: the alpha- and beta-domains. alpha-Domain mutations were significantly associated with a higher prevalence of retinal capillary hemangioblastomas (RCHs) compared with the beta-domain mutations (P=0.016). Among patients with RCHs, the prevalence of the lesions in the juxtapapillary position was also significantly higher in patients with alpha-domain mutations (P=0.0017). Conversely, beta-domain mutations correlated with a higher prevalence of peripherally located RCHs (P=0.0104).
  
  
  CONCLUSIONS
  The location of missense mutations in the VHL gene correlates significantly with the prevalence and phenotype of ocular disease, and as such, influences the risk of visual loss in affected patients. These genotype-phenotype correlations can assist in the prognostic counseling and follow-up of VHL patients and may provide a basis for molecular inferences on ocular VHL disease pathogenesis.
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, Office of the Scientific Director, and.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Mettu
authors.forename: Elvira
authors.initials: E
authors.lastname: Agrón
authors.forename: Sonia
authors.initials: S
authors.lastname: Samtani
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.forename: Wai T
authors.initials: WT
authors.lastname: Wong
mesh_terms: D000328:Adult; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D018324:Hemangioma, Capillary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D015995:Prevalence; D011379:Prognosis; D017434:Protein Structure, Tertiary / Q000235:genetics; D019572:Retinal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D014792:Visual Acuity; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human