© 1994 Oxford University Press
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Identification of intragenic mutations in the Von Hippel — Lindau disease tumour suppressor gene andcorrelation with disease phenotype
1Cambridge University Department of Pathology, Tennis Court Road, Cambridge CB2 1QP, UK, 1Division of Community Medicine, Memorial University of Newfoundl and Newfoundland A1B 3V6, Canada 2Laboratory of Immunobiology, NCI-FCRF Frederick, MD 21702–1201, USA
*To whom correspondence should be addressed at: University of Cambridge, Box 134, Addenbrooke‘s Hospital, Hills Road, Cambridge CB2 2QQ, UK
Received March 31, 1994; Accepted May 17, 1994
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal haemangloblas-toma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. We have previously detected large germline deletions by Southern analysis and pulsed field gel electrophoresls in 19% and 3% of VHL patients respectively. We have now investigated 94 VHL patients without large deletions for intragenic mutations using single strand conformation polymorphism and heteroduplex analysis. Forty different mutations were identified In 55 unrelated kindreds. A wide variety of mutations were detected Including mlssense (n = 19), nonsense (n = 6), frameshlft deletions or insertions (n = 12), in frame deletions (n = 2) and a splice donor site mutation (n = 1). The two most requent mutations, were mlssense mutations at codon 238 (Arg
Gin and ArgTrp) and were detected In five and four unrelated kindreds, respectively. VHL disease shows marked phenotypic variability and although phaeochromocytoma occurs in only about 7% of patients, marked interfamillal differences are observed. We examined the relationship between VHL gene mutations and phenotype in 65 kindreds. Large deletions or Intragenic mutations predicted to cause a truncated protein were found in 36 of 53 families without phaeochromocytoma but only two of 12 families with phaeochromocytoma (
2 = 8.58; P<0.01). Of 12 families with phaeochromocytoma 10 had missense mutations compared with 13 of 53 kindreds without phaeochromocytoma (2 =12.33; P<0.001). In particular, substitution of an arglnine at codon 238 (ArgTrp or ArgGIn) was associated with a high risk (62%) of phaeochromocytoma. The identification of germline mutations In VHL disease has provided a molecular correlation between genotype and phenotype, and a basis for gaining an insight Into the molecular basis for phenotypic variability in VHL disease.
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