Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma

Journal Article · Thu Dec 01 04:00:00 EST 1994 · American Journal of Human Genetics

OSTI ID:56720

Whaley, J M; Naglich, J; Gelbert, L; Laidlaw, J; Seizinger, B R; Kley, N ^[1]; Hsia, Y E ^[2]; Lamiell, J M ^[3]; Green, J S ^[4]; Collins, D ^[5]

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1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ (United States)
2. Univ. of Hawaii, Honolulu, HI (United States)
3. Brooke Army Medical Center, Fort Sam Houston, TX (United States)
4. Memorial Univ. of Newfoundland, St. Johns (Canada)
5. Univ. of Kansas Medical Center, Kansas City, KS (United States)

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation analyses and studied its expression in normal and tumor tissue. The authors identified germline mutations in 39% of VHL disease families. Moreover, 33% of sporadic RCCs and all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3{prime} end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3{prime} end of the known open reading frame.

• OSTI ID: 56720
• Journal Information: American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 6 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
CARCINOMAS
CHROMOSOMAL ABERRATIONS
DNA
GENE MUTATIONS
GENES
HEREDITARY DISEASES
HUMAN CHROMOSOMES
HUMAN POPULATIONS
NUCLEIC ACIDS
POLYMERASE CHAIN REACTION
SOMATIC MUTATIONS
TISSUE EXTRACTS