Seizinger B R, Smith D I, Filling-Katz M R, Neumann H, Green J S, Choyke P L, Anderson K M, Freiman R N, Klauck S M, Whaley J
Molecular Neuro-Oncology Laboratory, Massachusetts General Hospital, Boston 02114.
Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2864-8. doi: 10.1073/pnas.88.7.2864.
Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.
冯·希佩尔-林道病（VHL）是一种遗传性综合征，与多个器官系统中的肿瘤和囊肿相关，其表现和发病年龄高度可变。对于携带缺陷基因的个体，进行早期且可靠检测的基因检测方法对VHL患者及其亲属有益，因为VHL的许多表现若在早期被检测到，便可成功治疗，而未被检测出疾病的并发症可能是毁灭性的。我们之前已表明VHL基因定位于3号染色体短臂。为了开发可靠诊断测试提供遗传标记，并进一步缩小并最终克隆VHL缺陷基因，我们已生成了3号染色体短臂的DNA标记。利用这些标记，我们对28个VHL家系进行了多点遗传连锁分析，这些家系共470人，其中164人患有VHL。在此我们报告紧密连锁标记的鉴定，包括侧翼标记，这些标记将VHL基因定位于3号染色体短臂25 - 26区的一个小区域。这一发现有几个重要意义。虽然肾、胰腺和附睾的内脏囊肿在VHL中常见且被视为该疾病的诊断标准，但它们在普通人群中也会出现。因此，仅存在囊肿而无其他更典型病变（如视网膜和小脑成血管细胞瘤）可能代表一个主要诊断问题，导致疾病状态评估错误。将VHL基因的侧翼标记应用于症状前诊断测试证实，附睾囊肿确实不适合作该疾病的诊断标准。嗜铬细胞瘤在VHL家系中分布不均，也可能与其他遗传性肿瘤综合征相关；我们的遗传学研究表明，有或无嗜铬细胞瘤的VHL家系中的表型是由同一基因内的缺陷引起的。因此，这种肿瘤类型的有无是由于单个基因的多效性表达，而非存在几个不同的VHL基因。已知在“纯家族性肾细胞癌”家系中包含几个染色体易位断点的3号染色体短臂13 - 14区，与我们在3号染色体短臂25 - 26区鉴定的VHL基因座相当接近。因此，3号染色体可能包含两个肾细胞癌基因座：一个在3号染色体短臂13 - 14区的基因（或多个基因）和一个在3号染色体短臂25 - 26区的VHL基因，其畸变也与VHL的其他典型表现相关。由于肾细胞癌、嗜铬细胞瘤和内脏囊肿甚至在年轻人中也可能散发性出现，并且也可能与其他肿瘤综合征相关，VHL基因侧翼标记的可用性将有助于识别VHL基因携带者，特别是在那些有风险的个体中，这些症状是疾病的唯一表现。基于侧翼标记的鉴定对VHL基因进行分离和表征，将对VHL患者的诊断和治疗以及大量患有VHL相关肿瘤类型散发病例的个体具有重要意义。
