GERMLINE MUTATIONS IN THE VONHIPPEL-LINDAU DISEASE TUMOR-SUPPRESSOR GENE - CORRELATIONS WITH PHENOTYPE

von Hippel-Lindau disease (VHL) is an inherited neoplastic disease cha racterized by a predisposition to develop retinal angiomas, central ne rvous system hemangioblastomas, renal cell carcinomas, pancreatic cyst s, and pheochromocytomas. The VHL gene was recently isolated by positi onal cloning. The cDNA encodes 852 nucleotides in 3 exons. The VHL gen e is unrelated to any known gene families. We identified germline muta tions in 85/114 (75%) of VHL families. Clinical heterogeneity is a wel l known feature of VHL. VHL families were classified into 2 types base d on the presence or absence of pheochromocytoma. The types of mutatio ns responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Fif ty-six % of the mutations responsible for VHL type 1 were microdeletio ns/insertions, nonsense mutations, or deletions; 96% of the mutations responsible for VHL type 2 were missense mutations, Specific mutations in codon 238 accounted for 43% of the mutations responsible for VHL t ype 2, The mutations identified in these families will be useful in pr esymptomatic diagnosis. The identification of mutations associated wit h phenotypes contributes to the understanding of fundamental genetic m ech anisms of VHL disease. (C) 1995 Wiley Liss, Inc.