Phenotypic expression in von Hippel-Lindau disease: Correlations with germline VHL gene mutations
Phenotypic expression in von Hippel-Lindau disease: Correlations with germline VHL gene mutations
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DOI：
10.1136/jmg.33.4.328
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发表时间：
1996-04-01
影响因子：
4
通讯作者：
Moore, AT
中科院分区：
文献类型：
--
作者：
Maher, ER;Webster, AR;Moore, AT
Von Hippel-Lindau病是一种常染色体显性遗传的家族性癌症综合征，易患视网膜和中枢神经系统血管母细胞瘤、肾细胞癌和嗜铬细胞瘤。VHL疾病在嗜铬细胞瘤的易感性方面表现出可变的表达和家族间的差异。在以前的研究中，我们发现65 VHL激酶与定义VHL突变的VHL家族与非嗜铬细胞瘤，如错义突变更常见，大的缺失或蛋白质截短突变较少发生在嗜铬细胞瘤阳性家庭之间的显着差异。为了进一步研究这种关联的意义和原因，我们研究了138个VHL基因突变的种系激酶，并计算了不同类型VHL基因突变的年龄相关肿瘤风险。采用SSCP、异源双链和Southern分析，我们在101个家系（73%）中发现了生殖系VHL基因突变。VHL编码区的直接测序进一步将突变检测率提高到81%。除了精确的症状前诊断，VHL基因突变的鉴定可以提供可能的表型的指示。我们发现，预测导致截短蛋白的大缺失和突变与嗜铬细胞瘤的风险较低（30岁和50岁时分别为6%和9%），而错义突变（分别为40%和59%），密码子167的错义突变与嗜铬细胞瘤的高风险相关（30岁和50岁时分别为53%和82%）。肾细胞癌的累积概率在两组之间没有差异（在30岁和50岁时，缺失/截短突变分别为8%和60%，错义突变分别为10%和64%）。两个突变组中血管母细胞瘤的年龄相关风险相似，与年龄相关的小脑血管母细胞瘤风险略低（30岁和50岁时分别为35%和64% vs38%和75%）和视网膜血管母细胞瘤略高（45%和72%v37%和64%，在30岁和50岁）在错义突变组比缺失/蛋白质截短组。这些结果为咨询VHL家族提供了有价值的数据，并表明特定的VHL突变可能与不同的肿瘤易感性风险相关。没有证据表明错义突变的年龄相关肿瘤风险普遍增加，这表明易患嗜铬细胞瘤的错义突变具有组织特异性效应，可能是因为VHL蛋白具有多种功能，其重要性因组织而异，或者因为与VHL相互作用的蛋白质在不同组织之间不同。
Von Hippel-Lindau disease is an autosomal dominantly inherited familial cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL disease shows variable expression and interfamilial differences in predisposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences between VHL families with and without phaeochromocytoma such that missense mutations were more common and large deletions or protein truncating mutations less frequent in phaeochromocytoma positive families. To investigate the significance and cause of this association further, we studied 138 VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations. Using SSCP, heteroduplex and Southern analysis we identified a germline VHL gene mutation in 101 families (73%). Direct sequencing of the VHL coding region further increased the mutation detection rate to 81%. In addition to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59%, respectively) and that missense mutations at codon 167 were associated with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 50 years). Cumulative probabilities of renal cell carcinoma did not differ between the two groups (deletion/ truncation mutations: 8% and 60%, and missense mutations: 10% and 64% at ages 30 and 50 years, respectively). Age related risks for haemangioblastoma were similar in the two mutation groups, with the age related risks of cerebellar haemangioblastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 years) and retinal haemangioblastoma slightly higher (45% and 72% v 37% and 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL mutations may be associated with different tumour susceptibility risks. There was no evidence of a generalised increase in age related tumour risks for missense mutations, suggesting that missense mutations predisposing to phaeochromocytoma have tissue specific effects, possibly because the VHL protein has several functions, the importance of which varies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.