Unit on Neuron-Glia Interactions in Retinal Disease, Office of the Scientific Director, and.
Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4464-70. doi: 10.1167/iovs.10-5223. Epub 2010 Apr 7.
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.
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.
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).
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.
von Hippel-Lindau（VHL）病是一种显性遗传性多系统肿瘤综合征，由 VHL 基因突变引起。本研究旨在建立致病错义突变位置与 VHL 病眼部表型之间的基因型-表型相关性。
在一项横断面研究中（n=412），确定了具有临床定义的 VHL 病和 VHL 基因中记录的种系错义突变的参与者。使用统计分析将 VHL 蛋白的 alpha 或 beta 结构域中的错义突变位置与眼部疾病表型相关联。
研究参与者中的错义突变位于 VHL 基因 213 个可能密码子中的 47 个。几乎所有突变（98.5%）都位于 VHL 蛋白的两个结构域之一：alpha 和 beta 结构域。与 beta 结构域突变相比，alpha 结构域突变与视网膜毛细血管血管瘤（RCH）的更高患病率显著相关（P=0.016）。在患有 RCH 的患者中，alpha 结构域突变患者的病变在视盘旁位置的患病率也显著更高（P=0.0017）。相反，beta 结构域突变与更常见的周边 RCH 相关（P=0.0104）。
VHL 基因中错义突变的位置与眼部疾病的患病率和表型显著相关，因此影响了受影响患者的视力丧失风险。这些基因型-表型相关性可以辅助 VHL 患者的预后咨询和随访，并可能为眼部 VHL 疾病发病机制的分子推断提供基础。
