Identification of the von Hippel-Lindau disease tumor suppressor gene.

A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients and from sporadic renal cell carcinomas. The VHL gene is evolutionarily conserved and encodes two widely expressed transcripts of approximately 6 and 6.5 kilobases. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei.

[1]  P. Choyke,et al.  Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3. , 1990, Genomics.

[2]  Raymond White.  Inherited cancer genes , 1992 .

[3]  A. Knudson,et al.  Genetics of human cancer. , 1986, Annual review of genetics.

[4]  Margaret Robertson,et al.  Identification and characterization of the familial adenomatous polyposis coli gene , 1991, Cell.

[5]  D. Paslier,et al.  von Hippel-Lindau syndrome: cloning and identification of the plasma membrane Ca(++)-transporting ATPase isoform 2 gene that resides in the von Hippel-Lindau gene region. , 1993, Cancer research.

[6]  S. Altschul,et al.  Identification of FAP locus genes from chromosome 5q21. , 1991, Science.

[7]  M. Leppert,et al.  Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients , 1990, Cell.

[8]  M. Ferguson-Smith,et al.  Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. , 1990, Journal of medical genetics.

[9]  J. Fickett.  Recognition of protein coding regions in DNA sequences. , 1982, Nucleic acids research.

[10]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. Nakamura,et al.  Specific genetic change in tumors associated with von Hippel-Lindau disease. , 1989, Journal of the National Cancer Institute.

[12]  S. Klauck,et al.  Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Lisanti,et al.  Glycophospholipid membrane anchoring provides clues to the mechanism of protein sorting in polarized epithelial cells. , 1990, Trends in biochemical sciences.

[14]  J. Haines,et al.  Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma , 1988, Nature.

[15]  K. Kinzler,et al.  Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. , 1991, Science.

[16]  R. Weinberg,et al.  Tumor suppressor genes. , 1991, Science.

[17]  M. Lush,et al.  Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene. , 1993, Journal of medical genetics.

[18]  T. Sekiya,et al.  Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. , 1989, Genomics.

[19]  B. Brownstein,et al.  Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. , 1990, Science.

[20]  M. Ferguson.  Lipid anchors on membrane proteins , 1991 .

[21]  L. Schmidt,et al.  A genetic linkage map of 96 loci on the short arm of human chromosome 3. , 1992, Genomics.

[22]  N. Morton,et al.  Von Hippel-Lindau disease: a genetic study. , 1991, Journal of medical genetics.

[23]  G. Yancopoulos,et al.  The receptor for ciliary neurotrophic factor. , 1991, Science.

[24]  P. O'Connell,et al.  A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations , 1990, Cell.

[25]  J. Haines,et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor , 1993, Cell.