Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population
Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population
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DOI：
10.1111/j.1469-1809.2011.00647.x
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发表时间：
2011-07-01
影响因子：
1.9
通讯作者：
Murgia, Alessandra
中科院分区：
文献类型：
--
作者：
Leonardi, Emanuela;Martella, Maddalena;Murgia, Alessandra
VHL基因的突变失活是von Hippel-Lindau（VHL）病的原因，VHL病是一种常染色体显性遗传性癌症综合征，易患血管母细胞瘤、嗜铬细胞瘤和透明细胞肾癌。基因产物（pVHL）在细胞过程（包括细胞生长和凋亡）中作为衔接子发挥作用。在426名无关受试者中进行VHL突变分析，其表型范围从VHL综合征到可能代表该疾病首次表现的孤立VHL相关肿瘤。共有111个个体被发现携带变异，其中大的缺失占变异的40%。检测到的95种变体中有18种是新型的、看似致病的突变;已通过计算机模拟评估了它们的致病作用对蛋白质折叠和相互作用的影响。已经确定了pVHL和参与共同途径的蛋白质之间相互作用的推定区域，评估了这些区域中存在突变的可能影响。预测截断或导致pVHL结构完全丧失的所有新变体与VEIL 1型一致的表型相关。新的氨基酸替换中有7个是致病突变，一个是中性变异，而两个的结果仍然不明确。我们结合分子和计算机模拟的方法来评估推定的致病突变有助于解释这些新变异的潜在致病性。
Mutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VEIL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants.