Toward the isolation of the primary genetic defect in von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is a devastating hereditary tumor syndrome associated with various forms of cancer in multiple organ systems, including endothelial-derived tumors in the central nervous system, pheochromocytomas, and, a particularly frequent cause of death in VHL, renal cell carcinomas. Using DNA linkage analysis in a number of families displaying VHL, we recently showed that the primary defect in VHL maps to the short arm of chromosome 3. On the basis of the approximate knowledge of its chromosomal location, we have meanwhile bracketed this putative "tumor suppressor" gene to a small region of approximately 10 cM in chromosome 3p25-p26. The identification of closely linked flanking markers, together with the apparent genetic homogeneity of VHL, should allow for the development of a reliable diagnostic genetic test and provides the starting point for directed chromosomal "walking" and "jumping" toward the isolation of the defective gene itself. The characterization of the VHL gene should ultimately have important implications not only for patients with VHL, but also for a much larger number of cancer patients in the general population, afflicted with the sporadic counterparts of VHL-associated tumor types, such as renal cell carcinoma.