title: Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.
abstract: OBJECTIVE
  Intestinal neurofibromatosis (Online Mendelian inheritance in Man database number 162220) is an alternate form of neurofibromatosis. Patients present with neurofibromas limited to the intestine in the absence of any other typical features of NF1 and NF2. At present, the molecular basis of intestinal neurofibromatosis remains elusive. The aim of the present study was to find the gene responsible for intestinal neurofibromatosis and to characterize functionally the mutation.
  
  
  METHODS
  Three candidate genes (NF1, KIT, and PDGFRA) were screened for mutations in 3 sisters diagnosed with intestinal neurofibromatosis. Five tumors were available for pathologic examination. Activation (phosphorylation) of PDGFRalpha was subsequently tested by Western blot analysis on a transfected 293T and Ba/F3 cell line.
  
  
  RESULTS
  We found an inherited mutation (Y555C) in the juxtamembrane domain of PDGFRA in the affected individuals. The Y555C mutation leads to autophosphorylation and thus activation of PDGFRalpha. These observations confirm that PDGFRalpha(Y555C) is an oncogenic kinase. The clinical phenotype in the reported family resembles the syndrome of familial gastrointestinal stromal tumors (familial GIST). Somatic activating mutations in KIT and PDGFRA are frequent in sporadic GISTs, and mutations in both genes have also been described in familial GISTs. The tumors in the reported family are morphologically identical to intestinal neurofibromas, but, immunohistochemically, they do not express S100 or any of the known GIST markers.
  
  
  CONCLUSIONS
  The inherited PDGFRA mutation in the reported family shows that intestinal neurofibromatosis is allelic to familial GIST caused by PDGRA mutations. We therefore propose that these tumors be classified as familial KIT-negative gastrointestinal stromal tumors.
authors.affiliation: Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: de Raedt
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Hilde
authors.initials: H
authors.lastname: Brems
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Jacques
authors.initials: J
authors.lastname: Himpens
authors.forename: Ivo
authors.initials: I
authors.lastname: de Wever
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007410:Intestinal Diseases / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017253:Neurofibromatoses / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D004247:DNA; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha