Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.
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.
de Raedt
Thomas
T
Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
Cools
Jan
J
Debiec-Rychter
Maria
M
Brems
Hilde
H
Mentens
Nicole
N
Sciot
Raf
R
Himpens
Jacques
J
de Wever
Ivo
I
Schöffski
Patrick
P
Marynen
Peter
P
Legius
Eric
E
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
D004247:DNA; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha