Neurofibromatosis type 2 and von Hippel-Lindau disease: from gene cloning to function.

Most of the genes for hereditary tumor syndromes cloned thus far have subsequently been shown to be mutated not only in the germlines and tumors from patients with the relatively rare inherited disease, but also in the much more common sporadic tumor counterparts in the general population. Thus, the isolation and functional characterization of genes associated with hereditary tumor syndromes have emerged as a major strategy to gain insights into some of the most fundamental mechanisms of tumorigenesis. The search for the genes causing two hereditary tumor syndromes of the nervous system, neurofibromatosis type 2 (NF2) and von Hippel-Lindau disease (VHL), has recently culminated in the cloning of both disease genes. This represents another successful application of the so-called positional cloning approach, i.e., the isolation of a hereditary disease gene with unknown function, based on the determination of its chromosomal location in the human genome. The gene for NF2, a syndrome typically associated with vestibular schwannomas and meningiomas, is homologous with a family of genes whose members appear to play an important role in bridging the cell membrane with the intracellular cytoskeleton, including moesin, ezrin, radixin, and protein 4.1. Recent mutation analyses have revealed that the NF2 tumor suppressor gene is frequently mutated not only in vestibular schwannomas and meningiomas from NF2 patients, but also in their sporadic counterparts, which represent approximately one-third of all human brain tumors. Furthermore, malignant human tumors seemingly unrelated to the NF2 syndrome, such as neural crest-derived malignant melanomas, as well as malignant mesotheliomas (a pleural mesoderm-derived tumor), have also been found to be frequently mutated or deleted in the NF2 locus, suggesting a broader role for the NF2 gene in the initiation and progression of human neoplasms. VHL is a rare tumor syndrome characterized by certain types of nervous system tumors (cerebellar and spinal hemangioblastomas as well as retinal angiomas), in conjunction with bilateral renal cell carcinomas and pheochromocytomas. Similar to NF2, recent genetic mutation studies have revealed that the VHL tumor suppressor gene is not only mutated in the hereditary tumors from VHL patients, but also in their sporadic counterparts. Importantly, the VHL gene represents the most frequently mutated cancer-related gene thus far identified in sporadic renal cell carcinoma. In contrast to most other hereditary cancer syndromes, however, VHL mutations are surprisingly specific for tumors typically associated with the VHL syndrome, and have not been detected in any other tumor type unrelated to VHL. The cloning and initial genetic characterization of the NF2 and VHL genes have now provided a rational basis for subsequent functional studies on the elucidation of the normal and tumor-associated cellular signaling pathways of these tumor suppressor genes.