The von Hippel-Lindau (VHL) disease gene is a putative tumor-suppressor gene responsible for VHL disease, an autosomal dominantly inherited multitumor syndrome. The VHL-associated tumors and cysts include retinal angioma (RA), central nervous system (CNS) hemangioblastomas (HBs), renal cell carcinoma (RCC), pheochromocytoma (pheo), neuroendocrine tumors in the pancreas, and cysts in the kidney, pancreas, inner ear, epididymis and female reproductive organs. Clear cell RCC is a major risk of death in VHL disease [1]. The average age at the development of the kidney cancer in the VHL patients is 39.

The gene responsible for VHL disease was isolated by positional cloning at 3p25–26 by Latif et al.[2] in 1993. The isolated cDNA encodes 639 nucleotides (213 amino acids) in 3 exons as the coding region (fig. 1). The open reading frame has 2 start sites. The encoded proteins from the first or second start site are 24 and 19 kD, respectively. The 24-kD protein that actually migrates 30 kD in SDS gel is localized mainly in the cytosol and to a lesser degree in the nucleus. The 19-kD protein is equally distributed in the cytosol and nucleus [3–6]. It has specific acidic pentamer repeats at the top of exon 1 that has 48% homology with trypanozoma brucei (fig. 1).