Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis
Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis
复制标题
DOI：
10.1002/prot.22419
复制
发表时间：
2009-10-01
影响因子：
2.9
通讯作者：
Blundell, Tom L.
中科院分区：
文献类型：
--
作者：
Forman, Julia R.;Worth, Catherine L.;Blundell, Tom L.
VHL基因突变导致von Hippel-Lindau(VHL)病，这是一种临床上不同类型的癌症综合征。在这里，我们使用软件和数据库工具来了解和预测与VHL基因产物pVHL错义突变相关的表型。已知蛋白质产物pVHL与细长蛋白B、细长蛋白C和低氧诱导因子底物相互作用。通过分析已知和预测的相互作用位点，以及对突变后热力学稳定性变化的预测，我们对VHL疾病中肾细胞癌(RCC)和嗜铬细胞瘤(PCC)的分子病因学提出了新的假设。我们发现，RCC和PCC的分子病因似乎是解耦的。肾癌可能通过两种不同的机制发生：HIF相互作用的中断或细长蛋白B界面的结合。PCC是由破坏细长蛋白C结合位点的相互作用的突变触发的。这些发现对VHL病和非家族性肾癌有重要意义，因为大多数透明细胞RCC病例与VHL失活有关。此外，随着基因测序的加快，预测遗传变异的效果将是至关重要的；随着关于遗传变异的进一步数据的获得，这里提出的分析策略可能会阐明其他系统。
Mutations in the VHL gene lead to von Hippel-Lindau (VHL) disease, a clinically heterogeneous cancer syndrome. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the VHL gene product, pVHL. The protein product pVHL is known to interact with elongin B, elongin C, and the HIF substrate. By analyzing known and predicted interaction sites and predictions of thermodynamic stability change upon mutation, we generate new hypotheses regarding the molecular etiology of renal cell carcinoma (RCC) and pheochromocytoma (PCC) in VHL disease. We find that the molecular causes of RCC and PCC appear to be decoupled. RCC may arise through two distinct mechanisms: disruption of HIF interactions or binding at the elongin B interface. PCC is triggered by mutations which disrupt interactions at the elongin C binding site. These findings have important implications for VHL disease and for nonfamilial RCC, because most cases of clear cell RCC are linked with VHL inactivation. Additionally, predicting effects of genetic variation will be critical as genetic sequencing accelerates; the analytical strategy presented here may elucidate other systems as further data on genetic variation become available.