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P. Mettu, E. Agron, E. Y. Chew, W. T. Wong; Genotype-Phenotype Correlation in Ocular von Hippel-Lindau Disease: The Effect of Missense Mutation Position on Ocular Phenotype. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4100.
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© ARVO (1962-2015); The Authors (2016-present)
von Hippel-Lindau (VHL) disease is a multisystemic tumor syndrome with ocular manifestations caused by dominant mutations in the VHL gene. In this study, we established genotype-phenotype correlations between the position of disease-causing missense mutations and the ocular tumor phenotype of VHL disease.
Using a cross-sectional study design, we identified 412 VHL patients with germ-line missense mutations in the VHL gene. Of these, 157 patients had ocular involvement in the form of retinal capillary hemangioblastomas (RCHs). Statistical analysis was used to correlate the position of the missense mutation with RCH phenotype.
Missense mutations were located in 47 of 213 possible codons in the VHL gene. Of these, 98.5% were located in either of two structural domains, the and β domains. Mutations located in the -domain, compared to those in the β-domain, were correlated with a higher rate of RCHs (46% to 34%). For patients with RCHs, -domain mutations, compared to β-domain mutations, resulted in a higher prevalence of optic nerve RCHs (36% vs. 15%). Conversely, β-domain mutations led to a higher prevalence of peripherally located RCHs (90% vs. 77%). The location of mutations in vs. β domains did not significantly affect other aspects of RCH phenotype such as the age of onset, laterality, total RCH number, the extent of peripheral retina involved, or visual acuity. Stratification of missense mutations into those codons that are likely to affect elongin C protein binding did not reveal additional associations.
The location of missense mutations in the - vs. β-domain of the VHL gene had significant effects on the ocular phenotype, including the prevalence of ocular tumors in the form of RCH and also the position of RCHs within the eye. These genotype-phenotype correlations can assist in predicting the prevalence and nature of ocular VHL disease. Additionally, correlating the location of the missense mutations with ocular phenotype provides a basis for molecular inferences to be made about VHL protein function and the pathogenesis of ocular VHL disease.
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