Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: Correlations with phenotype

作者：Fan Chen, Takeshi Kishida, Masahiro Yao, Thomas P. Hustad, Damjan Glavač, Michael C. Dean, James R. Gnarra, Mary Lou Orcutt, Fuh Mei Duh, Gladys M. Glenn, Jane Green, Y. Edward Hsia, James M. Lamiell, Hua Li, Ming Hui Wei, Laura S. Schmidt, Kálmán Tory, Igor Kuzmin, Tom Stackhouse, Farida Latif, William Marston Linehan, Michael I. Lerman, Berton Zbar · 发表于：Human Mutation · 年份：1995 · DOI：10.1002/humu.1380050109 · 被引用次数：565 · 研究领域：Cancer, Hypoxia, and Metabolism、Fibroblast Growth Factor Research、Cancer-related Molecular Pathways

von Hippel-Lindau disease (VHL) is an inherited neoplastic disease characterized by a predisposition to develop retinal angiomas, central nervous system hemangioblastomas, renal cell carcinomas, pancreatic cysts, and pheochromocytomas. The VHL gene was recently isolated by positional cloning. The cDNA encodes 852 nucleotides in 3 exons. The VHL gene is unrelated to any known gene families. We identified germline mutations in 85/114 (75%) of VHL families. Clinical heterogeneity is a well-known feature of VHL. VHL families were classified into 2 types based on the presence or absence of pheochromocytoma. The types of mutations responsible for VHL without pheochromocytoma (VHL type 1) differed from those responsible for VHL with pheochromocytoma (VHL type 2). Fifty-six % of the mutations responsible for VHL type 1 were microdeletions/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 type 2. The mutations identified in these families will be useful in presymptomatic diagnosis. The identification of mutations associated with phenotypes contributes to the understanding of fundamental genetic mechanisms of VHL disease.