Molecular diagnosis of von Hippel-Lindau disease (VHL) using VHL tumor suppressor gene and the research for the VHL gene product

1996 Fiscal Year Final Research Report Summary

• Project/Area Number: 06671410
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Yokohama City University
• Principal Investigator: KANNO Hiroshi Yokohama City University School of Medicine, Assistant Professor, 医学部, 助手 (40244496)
• Co-Investigator(Kenkyū-buntansha): YAO Masahiro Yokohama City University School of Medicine, Assistant Professor, 医学部, 講師 (00260787) ; 執印 太郎 高知医科大学, 医学部, 教授 (80179019) ; YAMAMOTO Isao Yokohama City University School of Medicine, Professor & Chairman, 医学部, 教授 (30158266) ; FUJII Satoshi Yokohama City University School of Medicine, Associate Professor, 医学部, 助教授 (90173385) ; SHUIN Taro Kochi Medical School, Professor & Chairman
• Project Period (FY): 1994 – 1996
• Keywords: von Hippel-Lindau disease / VHL tumor suppressor gene / hemangioblastoma / molecular diagnosis / hereditary disease / 母斑病 / 血管芽種 / 遺伝性脳腫瘍

Research Abstract

To define the molecular basis of VHL patients in Japanese populations, we collected 72 unrelated Japanese VHL patients and completely tested for germline mutations of the VHL gene in 45 VHL patients by single-strand conformation polymorphism (SSCP) analysis and Southern blot analysis. We detected 23 (51%) intragenic mutations of the VHL gene and three (6.7%) deletions by SSCP analysis and Southern blot respectively. The intragenic mutations consisted of 14 missense mutations, seven microdeletions or insertions and two splice-site mutations. Nine of 10 mutations in exon 1 are localized in a short region of 37 nucleotides. Five unique sites of mutation were included, which were not seen in prevoius stuidied. Unlike Western VHL patients, nonsense mutations were not found in Japaneses VHL patients. The mutations found in 22 VHL patients without pheochromocytoma consisted of 11 missense mutations, six microdeletions or insertions, two splice-site alterations and three deletions. The mutations found in four VHL patients with pheochromocytomas consisted of one missense mutation at nucleotide 683 (codon 228), two missense mutations at uncleotide 712 (codon 38) and a novel 20 bp insertion at nucleotide 776 (codon 259). Our results suggest that unique features compared with those in Western patients.
In situ hybridyzation study with VHL gene probe showed expression of VHL gene at cerebral and cerebellar neuronal cells and stromal cells of hemangioblastoma. In addition, VHL protein expression with anti-VHL protein monoclonal antibody showed expression of VHL protein at neuronal cells and brain tumor cells.

Research Products

• [Publications] Kanno H,Shuin T,Kondo K,et al: "Somatic mutations of the von Hippel-Lindow Tumor sappressor gene and loss of heterozygosity on chromosome 3p in humun gilal tumors" Cancer Research. (発表予定). (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 菅野洋: "脳病変とvon Hippel-Lindau病" 病理と臨床. 15・2. 129-133 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kanno H,Shuin T,Kondo K,et al: "Molecular genetic diagnosis of von Hippel-Lindau disease:Analysis of five Japanese families" Japanese Journal of Cancer Research. 87. 423-428 (1996)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Clinical Research Group for VHL in Japan Shuin T,Yao M,Kanno H et al: "Germline mutations in the von Hippel-Lindau disease(VHL)gene in Japanese VHL" Human Molecular Genetics. 4・12. 2233-2237 (1995)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kanno H,Kondo K,Ito S,et al.: "Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas" Cancer Research. 54. 4845-4847 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shuin T,Kondo K,Torigoe S,et al: "Frequent somatic mutation and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal carclinomas" Cancer Research. 54. 2852-2854 (1994)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 1) Kanno H,Kondo K,Ito S,Yamamoto I,Fujii S,Torigoe S,Sakai N,Hosaka M,Shuin T,and Yao M: "Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangiobalstomas." Cancer Res. 54. 4845-4847 (1994)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 2) Shuin T,Yao M,Kanno H,et al. (Clinical Research Group for VHL in Japan): "Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL" Human Molecular Genetics. 4. 2233-2237 (1996)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 3) Kanno H,Shuin T,Kondo K,Ito S,Hosaka M,Torigoe S,Fujii S,Tanaka Y,Yamamoto I,Kim I,and Yao M: "Molecular genetic diagnosis of von Hippel-Lindau disease." Jpn J Cancer Res. 87. 423-428 (1996)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 4) Kanno H,Shuin T,Kondo K,Yamamoto I,Ito S,Shinonaga M,Yoshida M,and Yao M: "Somatic mutations of the von Hippel-Lindau tumor suppressor gene and loss of hetrozygosity on chromosome 3p in human glial tumors." Cancer Res. (in press). (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 5) Ito S,Kanno H,Kondo K,Shuin T,Hosaka M,Fujii S,Yamamoto I: Mutations and loss of heterozygosity of von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemngioblastomas. Brain Tumor Research and Therapy. Springer-Verlag, 277-282 (1995)
  • Description: 「研究成果報告書概要(欧文)」より