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首页> 外文期刊>Annals of Human Genetics >Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population
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Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population

机译：大量人群中新型von Hippel-Lindau（VHL）基因变异的鉴定和计算机分析

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摘要

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 VHL 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.
机译：VHL基因的突变失活是von Hippel-Lindau（VHL）疾病的病因，该疾病是常染色体显性遗传性癌症综合征，易患成血管母细胞瘤，嗜铬细胞瘤和透明细胞肾癌。基因产物（pVHL）在细胞生长和凋亡等细胞过程中起衔接子的作用。在426名不相关的受试者中进行了VHL突变分析，这些受试者的表型从VHL综合征到分离出的VHL相关肿瘤，可能代表该疾病的首发表现。发现总共111个人具有改变，其中大的缺失代表变体的40％。在检测到的95个变体中，有18个是新的看似引起疾病的突变。已通过计算机评估了它们的致病作用对蛋白质折叠和相互作用的影响。已经鉴定出pVHL与共同途径中涉及的蛋白质之间相互作用的推定区域，评估了这些区域中突变的存在的可能含义。预计将截断或完全导致pVHL结构丧失的所有新变体均与符合VHL 1型的表型相关。新的氨基酸替代中有7个是致病突变，一个是中性变体，而两个的结果仍然不明确。我们结合分子和计算机模拟方法对推定的致病突变进行评估，有助于解释这些新型变异的潜在致病性。

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