GERMLINE MUTATION PROFILE OF THE VHL GENE IN VON-HIPPEL-LINDAU-DISEASE AND IN SPORADIC HEMANGIOBLASTOMA

Von Hippel-Lindau (VHI;) disease is a dominantly inherited disorder pr edisposing those afflicted to hemangioblastomas of the central nervous system and the retina, renal cell carcinomas, pheochromocytomas, and pancreatic tumors. The disease has been associated with mutations of t he VHL gene. The screening of 92 unrelated patients with VHL disease f or point mutations in this gene revealed 61 DNA variants. In addition, a search for EcoR1 rearrangements revealed germline anomalies in 5 pa tients. The 61 variants could be subdivided in 20 mutations predicted to alter the open reading frame (8 nonsense mutations, 8 frame shift m utations, and 4 mutations in consensus splicing sites) and 43 DNA sequ ence variants of a priori unknown biological consequence (4 in frame i nsertions or deletions, 36 missense mutations, and 3 apparently silent variations). The 3' end of the coding sequence of the VHL gene, which encodes the Elongin binding domain was the site of 5 of 20 truncating mutations (25%) and of 18 of 41 DNA variants (44%) causing uncertain functional impairment. A similar screening in 18 patients with sporadi c hemangioblastoma revealed 2 missense DNA variants. In order to corro borate this latter observation, a systematic screening for germline al teration of the VHL gene might be performed in a larger series of spor adic hemangioblastoma. If this preliminary result is confirmed, more t han 10% of sporadic hemangioblastoma might be related to a mild VHL di sease, thus a follow-up program similar to that recommended in cases o f VHI, disease should probably be discussed in the corresponding famil ies. Hum Mutat 12:424-430, 1998. (C) 1998 Wiley-Liss, Inc.