title: A mutation at IVS1 + 5 of the von Hippel-Lindau gene resulting in intron retention in transcripts is not pathogenic in a patient with a tongue cancer?: case report.
abstract: BACKGROUND
  Von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing the patient to a variety of malignant and benign neoplasms, most frequently hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors. VHL is caused by mutations of the VHL tumor suppressor gene on the short arm of chromosome 3, and clinical manifestations develop if both alleles are inactivated according to the two-hit hypothesis. VHL mutations are more frequent in the coding region and occur occasionally in the splicing region of the gene. Previously, we reported that the loss of heterozygosity (LOH) of the VHL gene is common in squamous cell carcinoma tissues of the tongue.
  
  
  METHODS
  We describe a case of squamous cell carcinoma in the tongue caused by a point mutation in the splicing region of the VHL gene and discuss its association with VHL disease. Sequence analysis of DNA extracted from the tumor and peripheral blood of the patient with squamous cell carcinoma revealed a heterozygous germline mutation (c. 340 + 5 G > C) in the splice donor sequence in intron 1 of the VHL gene. RT-PCR analysis of the exon1/intron1 junction in RNA from tumor tissue detected an unspliced transcript. Analysis of LOH using a marker with a heterozygous mutation of nucleotides (G or C) revealed a deletion of the mutant C allele in the carcinoma tissues.
  
  
  CONCLUSIONS
  The fifth nucleotide G of the splice donor site of the VHL gene is important for the efficiency of splicing at that site. The development of tongue cancer in this patient was not associated with VHL disease because the mutation occurred in only a single allele of the VHL gene and that allele was deleted in tumor cells.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Asakawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Esumi
authors.forename: Sohei
authors.initials: S
authors.lastname: Endo
authors.forename: Akinori
authors.initials: A
authors.lastname: Kida
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014062:Tongue Neoplasms / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D017931:DNA Primers; D051794:Von Hippel-Lindau Tumor Suppressor Protein