Role of VHL tumor suppressor gene in central nervous system

Von Hippel-Lindau病(VHL)是一种常染色体显性遗传性疾病，发生于中枢神经系统和视网膜的血管母细胞瘤、肾细胞癌和嗜铬细胞瘤。致病基因已于1993年从3p染色体上分离出来。我们不仅在散发性血管母细胞瘤和肾细胞瘤中发现了体细胞性VHL基因突变，而且在胶质瘤中也发现了VHL基因突变。此外，我们还通过DNA分析对80个日本VHL家系进行了分子遗传学诊断。VHL基因及其产物表达于中枢神经系统神经元、近端肾小管、血管母细胞瘤和神经胶质瘤的胞浆中。然而，病理上恶性程度越高的胶质瘤，VHL基因产物的表达就越少。在神经干细胞的神经元发育过程中，VHL基因的表达与神经元分化密切相关。此外，VHL基因还下调了神经干细胞的细胞周期。

Von Hippel-Lindau disease (VHL) is an autosomal dominant hereditary disease which develops hamangioblastomas in the central nervous system and retina, renal cell carcinoma, and pheochromocytoma. The causative gene has been isolated from chromosome 3p in 1993. We have found somatic VHL gene mutations in not only sporadic hemangioblastomas and renal cell but also gliomas. In addition, we have performed molecular genetic diagnosis of 80 Japanese VHL families by the DNA analyses. The expressions of VHL gene and product were identified at neuron in the central nervous system and proximal renal tubule as well as cytoplasm of hemangiobalstoma and glioma. However, pathologically more malignant gliomas showed less expression of VHL gene produst. In process of neuronal development, VHL gene expressions were correlated with neuronal differentiation in neural stem cells. In addtion, it was suggested that cell cycle of neural stem cells were down-regulated by VHL gene.