Document Detail

Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype.
MedLine Citation:
PMID:  20375333     Owner:  NLM     Status:  MEDLINE    
PURPOSE: 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.
Pradeep Mettu; Elvira Agrón; Sonia Samtani; Emily Y Chew; Wai T Wong
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2010-04-07
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  51     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-31     Completed Date:  2010-10-04     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4464-70     Citation Subset:  IM    
Unit on Neuron-Glia Interactions in Retinal Disease, Office of the Scientific Director, and.
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MeSH Terms
Cross-Sectional Studies
Follow-Up Studies
Genetic Counseling
Genetic Predisposition to Disease / epidemiology
Hemangioma, Capillary / epidemiology,  genetics*,  pathology
Middle Aged
Mutation, Missense*
Protein Structure, Tertiary / genetics
Retinal Neoplasms / epidemiology,  genetics*,  pathology
Visual Acuity
Von Hippel-Lindau Tumor Suppressor Protein / chemistry,  genetics*
Young Adult
von Hippel-Lindau Disease / epidemiology,  genetics*,  pathology
Grant Support
Reg. No./Substance:
EC protein, human; EC Hippel-Lindau Tumor Suppressor Protein

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