title: The N131S mutation in the von Hippel-Lindau gene in a Japanese family with pheochromocytoma and hemangioblastomas.
abstract: von Hippel-Lindau (VHL) disease (VHLD) is a hereditary autosomal dominant syndrome that causes various benign and malignant tumors. VHLD is caused by mutations in the VHL tumor suppressor gene. Here, we report a mutation in the VHL gene in a Japanese family with VHLD type 2A, characterized by pheochromocytoma (PHE), and hemangioblastomas (HAB) in both the retina and thoracic spinal cord but without renal cell carcinoma (RCC). We identified a heterozygous A to G point mutation at the second base of codon 131 of the VHL protein (pVHL). This mutation was predicted to convert codon 131 from asparagine to serine (N131S). Although most mutations in VHLD type 2A have been detected in the alpha domain of pVHL, the present mutated amino acid was located at the region encoding the beta domain of pVHL. Previous patients with the N131K or N131T mutation in pVHL developed VHLD type 2B with RCC or VHLD type 1 without PHE, respectively. We also identified somatic loss of heterozygosity (LOH) at chromosome 3p25-26 in the adrenal tumor of the patient. The results of our study suggest that not only the location of mutation but also the altered amino acid may be critical for determining the clinical phenotype of VHLD. LOH was associated with the development of PHE in a patient with the N131S mutation in pVHL.
authors.affiliation: Division of Endocrinology/Metabolism, Neurology, and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Imanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Iida
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsuji
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Fukuoka
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takeno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Okimura
authors.forename: Hidesuke
authors.initials: H
authors.lastname: Kaji
authors.forename: Kazuo
authors.initials: K
authors.lastname: Chihara
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000235:genetics*; D000328:Adult; D044466:Asian People; D002528:Cerebellar Neoplasms / Q000150:complications / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D018325:Hemangioblastoma / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010673:Pheochromocytoma / Q000150:complications / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein