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Abstract

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.

References

CAWTHON, R.M., A MAJOR SEGMENT OF THE NEUROFIBROMATOSIS TYPE-1 GENE - CDNA SEQUENCE, GENOMIC STRUCTURE, AND POINT MUTATIONS, CELL 62: 193 (1990).
Church, G. M., Proceedings of the National Academy of Sciences of the United States of America 81: 1991 (1984).
Crossey, P. A., Human Molecular Genetics 2: 279 (1993).
DAVIS, S, THE RECEPTOR FOR CILIARY NEUROTROPHIC FACTOR, SCIENCE 253: 59 (1991).
DEAN, M, MULTIPLE MUTATIONS IN HIGHLY CONSERVED RESIDUES ARE FOUND IN MILDLY AFFECTED CYSTIC-FIBROSIS PATIENTS, CELL 61: 863 (1990).
DOOLITTLE, R.F., RECONSTRUCTING HISTORY WITH AMINO-ACID-SEQUENCES, PROTEIN SCIENCE 1: 191 (1992).
FERGUSON, MAJ, CURR OPIN STRUC BIOL 1: 522 (1991).
FICKETT, J.W., RECOGNITION OF PROTEIN CODING REGIONS IN DNA-SEQUENCES, NUCLEIC ACIDS RESEARCH 10: 5303 (1982).
GLENN, G.M., VONHIPPEL-LINDAU (VHL) DISEASE - DISTINCT PHENOTYPES SUGGEST MORE THAN ONE MUTANT ALLELE AT THE VHL LOCUS, HUMAN GENETICS 87: 207 (1991).
GRODEN, J, IDENTIFICATION AND CHARACTERIZATION OF THE FAMILIAL ADENOMATOUS POLYPOSIS-COLI GENE, CELL 66: 589 (1991).
HOSOE, S, LOCALIZATION OF THE VONHIPPEL-LINDAU DISEASE GENE TO A SMALL REGION OF CHROMOSOME-3, GENOMICS 8: 634 (1990).
KINZLER, K.W., IDENTIFICATION OF FAP LOCUS GENES FROM CHROMOSOME-5Q21, SCIENCE 253: 661 (1991).
KNUDSON, A.G., GENETICS OF HUMAN CANCER, ANNUAL REVIEW OF GENETICS 20: 231 (1986).
KNUDSON, A.G., MUTATION AND CANCER - STATISTICAL STUDY OF RETINOBLASTOMA, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 68: 820 (1971).
LATIF, F, VHL is located close to D3S601 in the interval between RAF1 and D3S18, AMERICAN JOURNAL OF HUMAN GENETICS 51 Supplement: A63 (1992).
LATIF, F, VONHIPPEL-LINDAU SYNDROME - CLONING AND IDENTIFICATION OF THE PLASMA-MEMBRANE CA++-TRANSPORTING ATPASE ISOFORM-2 GENE THAT RESIDES IN THE VONHIPPEL-LINDAU GENE REGION, CANCER RESEARCH 53: 861 (1993).
LISANTI, M.P., GLYCOPHOSPHOLIPID MEMBRANE ANCHORING PROVIDES CLUES TO THE MECHANISM OF PROTEIN SORTING IN POLARIZED EPITHELIAL-CELLS, TRENDS IN BIOCHEMICAL SCIENCES 15: 113 (1990).
MAHER, E.R., GENOMICS 10: 957 (1991).
MAHER, E.R., STATISTICAL-ANALYSIS OF THE 2 STAGE MUTATION MODEL IN VONHIPPEL-LINDAU DISEASE, AND IN SPORADIC CEREBELLAR HEMANGIOBLASTOMA AND RENAL-CELL CARCINOMA, JOURNAL OF MEDICAL GENETICS 27: 311 (1990).
MAHER, E.R., VONHIPPEL-LINDAU DISEASE - A GENETIC-STUDY, JOURNAL OF MEDICAL GENETICS 28: 443 (1991).
MAHER, E.R., unpublished data.
McKusick, V. A., Mendelian Inheritance in Man 6 534 (1983).
MOWATT, M.R., VARIATION OF TANDEM REPEATS IN THE DEVELOPMENTALLY REGULATED PROCYCLIC ACIDIC REPETITIVE PROTEINS OF TRYPANOSOMA-BRUCEI, MOLECULAR AND CELLULAR BIOLOGY 9: 1332 (1989).
NISHISHO, I, MUTATIONS OF CHROMOSOME-5Q21 GENES IN FAP AND COLORECTAL-CANCER PATIENTS, SCIENCE 253: 665 (1991).
ORITA, M, RAPID AND SENSITIVE DETECTION OF POINT MUTATIONS AND DNA POLYMORPHISMS USING THE POLYMERASE CHAIN-REACTION, GENOMICS 5: 874 (1989).
Pearson, W. R., Proceedings of the National Academy of Sciences of the United States of America 85: 2444 (1988).
RICHARDS, F.M., DETAILED GENETIC-MAPPING OF THE VONHIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR GENE, JOURNAL OF MEDICAL GENETICS 30: 104 (1993).
SEIZINGER, B.R., VONHIPPEL-LINDAU DISEASE MAPS TO THE REGION OF CHROMOSOME-3 ASSOCIATED WITH RENAL-CELL CARCINOMA, NATURE 332: 268 (1988).
SEIZINGER, B.R., GENETIC FLANKING MARKERS REFINE DIAGNOSTIC-CRITERIA AND PROVIDE INSIGHTS INTO THE GENETICS OF VONHIPPEL LINDAU DISEASE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 88: 2864 (1991).
TORY, K, A GENETIC-LINKAGE MAP OF 96-LOCI ON THE SHORT ARM OF HUMAN CHROMOSOME-3, GENOMICS 13: 275 (1992).
TORY, K, SPECIFIC GENETIC CHANGE IN TUMORS ASSOCIATED WITH VONHIPPEL-LINDAU DISEASE, JOURNAL OF THE NATIONAL CANCER INSTITUTE 81: 1097 (1989).
TRAFATTER, J.A., CELL 72: 791 (1993).
VANCE, J. M., AMERICAN JOURNAL OF HUMAN GENETICS 51 Supplement: 203 (1992).
WALLACE, M.R., TYPE-1 NEUROFIBROMATOSIS GENE - IDENTIFICATION OF A LARGE TRANSCRIPT DISRUPTED IN 3 NF1 PATIENTS, SCIENCE 249: 181 (1990).
WEINBERG, R.A., TUMOR SUPPRESSOR GENES, SCIENCE 254: 1138 (1991).
WHITE, R, CURR OPIN GENE DEV 2: 53 (1992).
Yao, M, Human Genetics 92: 605 (1993).
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Science
Volume 260 | Issue 5112
28 May 1993

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Published in print: 28 May 1993

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Affiliations

Farida Latif
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
Kalman Tory
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
James Gnarra
Surgery Branch, NCI, Bethesda, MD 20892.
Masahiro Yao
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
Fuh-Mei Duh
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Mary Lou Orcutt
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
Thomas Stackhouse
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Igor Kuzmin
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
William Modi
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Laura Geil
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Laura Schmidt
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Fangwei Zhou
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
Hua Li
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Ming Hui Wei
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Fan Chen
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Gladys Glenn
Cancer Diagnosis Branch, NCI, Bethesda, MD 20892.
Peter Choyke
Clinical Center, Department of Radiology, NCI, Bethesda, MD 20892.
McClellan M. Walther
Surgery Branch, NCI, Bethesda, MD 20892.
Yongkai Weng
Surgery Branch, NCI, Bethesda, MD 20892.
Dah-Shuhn R. Duan
Surgery Branch, NCI, Bethesda, MD 20892.
Michael Dean
Laboratory of Viral Carcinogenesis, NCIFCRDC, Frederick, MD 21702-1201.
Damjan Glavač
Program Resources, Inc./DynCorp, NCI-FCRDC, Frederick, MD 21702-1201.
Frances M. Richards
Department of Pathology, Cambridge University, Cambridge CB2 1QP, United Kingdom.
Paul A. Crossey
Department of Pathology, Cambridge University, Cambridge CB2 1QP, United Kingdom.
Malcolm A. Ferguson-Smith
Department of Pathology, Cambridge University, Cambridge CB2 1QP, United Kingdom.
Denis Le Paslier
Centre d'Etude du Polymorphisme Humain, Paris F-75010, France.
llya Chumakov
Centre d'Etude du Polymorphisme Humain, Paris F-75010, France.
Daniel Cohen
Centre d'Etude du Polymorphisme Humain, Paris F-75010, France.
A. Craig Chinault
Institute for Molecular Genetics, Baylor College of Medicine, Houston, TX 77030
Eamonn R. Maher
Department of Pathology, Cambridge University, Cambridge CB2 1QP, United Kingdom.
W. Marston Linehan
Surgery Branch, NCI, Bethesda, MD 20892.
Berton Zbar
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.
Michael I. Lerman
Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center (NCI-FCRDC), Frederick, MD 21702-1201.

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