title: Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma.
abstract: von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients.
  
  
  
  Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated.
  
  
  
  We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05).
  
  
  
  This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Jee-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Kyu Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Joon Mo
authors.initials: JM
authors.lastname: Hong
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Ra
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Man Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea.
authors.forename: Sung Sup
authors.initials: SS
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. mwseong@snu.ac.kr.
authors.forename: Moon-Woo
authors.initials: MW
authors.lastname: Seong
mesh_terms: D000293:Adolescent; D000328:Adult; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D018325:Hemangioblastoma / Q000209:etiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D056910:Republic of Korea; D012306:Risk; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D006623:von Hippel-Lindau Disease / Q000150:complications* / Q000235:genetics* / Q000473:pathology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein
keywords: Genotype-phenotype correlation; Hypoxia-inducible factor 1; von Hippel-Lindau Tumor suppressor protein; von Hippel-Lindau disease