Identification of two sporadically derived mutations in the Von Hippel-Lindau gene

✍ Scribed by Roger L. Martin; Ian Walpole; Jack Goldblatt

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 99 KB
• Volume: 7
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/(sici)1098-1004(1996)7:2<185::aid-humu22>3.0.co;2-y

✦ Synopsis

Von Hippel-Lindau disease is an autosomal dominantly inherited disorder characterised by the development of haemangioblastomas, renal carcinomas, retinal angiomata, pancreatic tumours, and phaeochromocytomas . The tumour suppressor gene responsible for VHL has been mapped to 3p25 and a partial sequence of the cDNA has been characterised .

In this study two unrelated patients presenting with features of VHL, with no prior family history, were screened for mutations in the gene. The two patients genotypes and phenotypes are shown in Table . The three published exons of the VHL gene were amplified by PCR from genomic DNA and the products screened by SSCP for conformational changes that were seen in the products from exon 3 in both cases.

Sequences analysis of exon 3 for M revealed an heterozygous T > C point mutation at base 697, which results in a C > R substitution at codon 233 (Table ), which was not present in either parent. This mutation has recently been reported . With patient W, the mutation was novel, being a heterozygous G > A intronic point mutation at base 677-1, which results in a loss of exon 3's splice acceptor site, i.e., ccagTGTA to ccaaTGTA (Table ). W s parents were unavailable for testing.

These results continue the association between mutations in the VHL gene and the VHL phenotype. They indicate that the published exons are a "hotspot" for mutations. So, whereas the complete cDNA has not been fully characterised, screening of patients for mutations in the three published exons by SSCP appears to be an effective strategy. In addition, screening of patients with symptoms of VHL but who have no family history is also warranted, as our results suggest that sporadic germline mutation of the tumour suppressor gene does occur.