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Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype
- Source :
- Human molecular genetics. 3(8)
- Publication Year :
- 1994
-
Abstract
- 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 haemangioblastoma, renal cell carcinoma, phaeochromocytoma and pancreatic tumours. We have previously detected large germline deletions by Southern analysis and pulsed field gel electrophoresis 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 missense (n = 19), nonsense (n = 6), frameshift deletions or insertions (n = 12), in frame deletions (n = 2) and a splice donor site mutation (n = 1). The two most frequent mutations, were missense mutations at codon 238 (Arg--Gln and Arg--Trp) 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 interfamilial 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 (chi 2 = 8.58; P0.01). Of 12 families with phaeochromocytoma 10 had missense mutations compared with 13 of 53 kindreds without phaeochromocytoma (chi 2 = 12.33; P0.001). In particular, substitution of an arginine at codon 238 (Arg--Trp or Arg--Gln) was associated with a high risk (62%) of phaeochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)
- Subjects :
- von Hippel-Lindau Disease
endocrine system diseases
Molecular Sequence Data
medicine.disease_cause
Frameshift mutation
Von Hippel–Lindau tumor suppressor
Genetics
medicine
Missense mutation
Humans
Genes, Tumor Suppressor
Von Hippel–Lindau disease
Molecular Biology
Genetics (clinical)
Polymorphism, Single-Stranded Conformational
Mutation
biology
Base Sequence
Point mutation
Single-strand conformation polymorphism
General Medicine
DNA
Exons
medicine.disease
Phenotype
biology.protein
VHL Gene Mutation
Subjects
Details
- ISSN :
- 09646906
- Volume :
- 3
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....5bd587c060019850ca24238567c88972