title: Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.
abstract: BACKGROUND
  Gain-of-function mutations of the c-kit protooncogene, mainly clustered in the juxtamembrane domain, have been reported in a significant fraction of gastrointestinal (GI) stromal tumors (GISTs) that represent the most common mesenchymal tumor of the GI tract. Two families also have been described with a GIST predisposition syndrome with a germline c-kit mutation affecting either the juxtamembrane domain or the tyrosine kinase domain. Here, the authors report on a family in which the dominantly inherited trait of hyperpigmented spots was inherited from an individual who developed multiple GISTs with diffuse hyperplasia of the myenteric plexus by his son, who was affected with urticaria pigmentosa.
  
  
  METHODS
  Screening for the c-kit mutation was performed by means of polymerase chain reaction-based denaturing gradient gel electrophoresis/constant denaturing gel electrophoresis followed by direct sequencing of abnormal conformers. Expression of KIT and CD34 was determined by immunohistochemistry.
  
  
  RESULTS
  In peripheral blood DNA samples, both affected family members showed a previously undescribed c-kit mutation in the juxtamembrane domain, resulting in the substitution of alanine for valine(559). Mutation and polymorphic marker analyses on DNA samples from three GISTs and two skin biopsy specimens evidenced the same mutation in the heterozygous condition. Immunohistochemical examination showed coexpression of CD117 (c-kit) and CD34 in all independent GISTs and CD117 positivity in mast cells from the skin lesions.
  
  
  CONCLUSIONS
  Comparative analysis of clinical presentation and mutation mapping in the families described to date point to the peculiar association of mast cells, melanocytic dysfunction, and GIST predisposition in carriers of c-kit mutations within the juxtamembrane domain.
authors.affiliation: Department of Biology and Genetics, Medical Faculty, University of Milan, via Viotti 3/5, 20133 Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Beghini
authors.forename: M G
authors.initials: MG
authors.lastname: Tibiletti
authors.forename: G
authors.initials: G
authors.lastname: Roversi
authors.forename: A M
authors.initials: AM
authors.lastname: Chiaravalli
authors.forename: G
authors.initials: G
authors.lastname: Serio
authors.forename: C
authors.initials: C
authors.lastname: Capella
authors.forename: L
authors.initials: L
authors.lastname: Larizza
mesh_terms: D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015513:Oncogene Proteins / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit; D017154:Stromal Cells / Q000473:pathology; D014582:Urticaria Pigmentosa / Q000235:genetics* / Q000473:pathology
chemical_list: D015513:Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit