Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family

Von Hippel-Lindau disease (VHL) (OMIM nr. 193300) is a rare autosomal dominant multi-organ disease caused by molecular abnormalities of the VHL tumor suppressor gene [1]. Patients with VHL are at risk for development of retinal, cerebellar, spinal, pancreatic and renal hemangioblastomas, pulmonary and liver hemangiomas, clear-cell renal carcinomas, pheochromocytomas, endolymphatic sac tumors, multiple renal, epididymal and pancreatic cysts, cystadenomas of the epididymis and of the broad ligament, and pancreatic islet cell tumors [1-3]. Based on the presence or absence of pheochromocytoma, two main subtypes of the VHL disease have been identified. Patients with VHL type 1 are at risk to develop renal cell carcinoma and hemangioblastoma but predominantly without pheochromocytoma, while those with VHL type 2 may have all manifestations of the disease predominantly including pheochromocytoma. VHL type 2 has been subdivided into subtype 2A and 2B, with a low and high risk of renal cell carcinoma, respectively, whereas subtype 2C is a pheochromocytoma-only phenotype. The prevalence of the VHL disease varies between 1:39,000 in Germany and 1:53,000 in East Anglia [4,5]. Manifestations of the disease show variable expression and several patients may have only one manifestation [4].The human VHL gene maps to chromosome 3p25-26 [1]. As predicted by Knudson's two-hit model, tumor development requires inactivation of both copies; the first hit, the germline mutation or deletion is followed by somatic alterations usually detected as loss of heterozygosity. The VHL gene has two translational initiation sites separated by 53 codons. Of the two proteins encoded by the VHL gene, the larger one contains 213 amino acids (pVHL30), whereas the shorter protein consists of 160 amino acids (pVHL18). Both proteins are functionally active and they share the same mechanism of tumor suppressor activity [6-8]. The VHL proteins form a multimeric complex with Elongin B, Elongin C, Cul2 and Rbx1.