Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions
Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions
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DOI：
10.1002/humu.20082
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发表时间：
2004-01-01
期刊：
影响因子：
3.9
通讯作者：
Béroud, C
中科院分区：
文献类型：
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作者：
Gallou, C;Chauveau, D;Béroud, C
von Hippel-Lindau（VHL）病由VHL基因突变引起，并使患者易于在不同器官中发生各种肿瘤。在肾脏中，可能发生单个或多个囊肿和肾细胞癌（RCC）。临床表现的家族间和家族内异质性已得到公认。为了确定VHL依赖的遗传因素，我们调查了来自126个无关VHL家族的274个个体的肾脏表型，其中92种不同的VHL突变被表征。与错义突变的家族相比，突变导致截短蛋白（MLTP）或大重排的家族中肾脏受累的发生率增加（分别为81%和63%; P = 0.03）。在后一组中，我们确定了两个与肾脏病变高风险相关的突变簇区域（MCR）：MCR-1（密码子74-90）和MCR-2（密码子130-136）。此外，肾细胞癌的发病率在MLTP的家庭高于在家庭的错义变化（75比57%; P = 0.04）。此外，MCR-1而不是MCR-2内的突变赋予了发生RCC的遗传易感性。总体而言，我们的数据认为VHL基因的遗传变化对VHL患者肾脏表型的易感性有重大贡献。(C)2004 Wiley-Liss，Inc.
von Hippel-Lindau (VHL) disease arises from mutations in the VHL gene and predisposes patients to develop a variety of tumors in different organs. In the kidney, single or multiple cysts and renal cell carcinomas (RCC) may occur. Both inter, and intrafamilial heterogeneity in clinical expression are well recognized. To identify VHL-dependent genetic factors, we investigated the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were characterized. The incidence of renal involvement was increased in families with mutations leading to truncated protein (MLTP) or large rearrangement, as compared to families with missense changes (81 vs. 63%, respectively; P = 0.03). In the latter group, we identified two mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCC was higher in families with MLTP than in families with missense changes (75 vs. 57%; P = 0.04). Furthermore, mutations within MCR-1 but not MCR-2 conferred genetic susceptibility to develop RCC. Overall, our data argued for a substantial contribution of the genetic change in the VHL gene to susceptibility to renal phenotype in VHL patients. (C) 2004 Wiley-Liss, Inc.