Genotype Phenotype correlation and molecular mechanisms of hemangioblastoma manifestation in VHL Syndrome

Abstract

The general prevalence of the familial multiorgan tumor disorder, von Hippel Lindau syndrome (VHL), has been estimated to be 1 in 25 40,000 in western countries two decades ago. Studies from the Indian sub-continent remain scarce and limited to clinical reports on VHL-specific manifestations. The syndrome results from mutations of the gene VHL (located in Chr 3p25.3) and is an autosomal dominant disorder with marked phenotypic variability and age dependent penetrance. VHL has most frequent manifestations namely CNS hemangioblastoma, retinal angioma, clear cell renal cell carcinoma, endo lymphatic sac tumor, pancreatic islet tumor and multicystic panceres. We aimed to conduct a prospective case series describing phenotypic and genotypic characteristics in Indian population. About 60 80 % of subjects with VHL syndrome develop central nervous system hemangioblastomas, vascular tumors composed of a thick network of blood vessels and pericytes. VHL protein forms heteromeric complexes with Elongin B, Elongin C and Cullin proteins that bind to Hypoxia Inducible Factor 1 alpha (HIF1A) on its hydroxylated proline residues to direct a regulated proteolysis of HIF1A. At lower oxygen concentrations, regulated hydroxylation of proline rescues HIF-1and#945; to induce a set of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF), Glucose transporter-1 (GLUT1) and Erythropoietin (EPO) causing endothelial cell proliferation and neovascularization. Truncating or disruptive inherited mutations of the VHL gene causing lack of functional VHL protein lead to uninhibited HIF-1and#945; directed induction of hypoxia-inducible genes thought to lead to angiogenesis and ultimately hemangioblastoma (HB). However, we and others have shown from germline mutational analysis that many disruptive mutations of VHL gene would not necessarily lead to HBand#8288;. Other manifestations of VHL syndrome such as cystic organ damage of liver, pancreas, and kidney are not widely understood. Part I of the present study was intended to describe ..