Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Intestinal Neurofibromatosis Is a Subtype of Familial GIST and Results From a Dominant Activating Mutation in PDGFRA
Ist Teil von
Gastroenterology (New York, N.Y. 1943), 2006-12, Vol.131 (6), p.1907-1912
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2006
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Background & Aims:
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 PDGFRα 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 PDGFRα. These observations confirm that PDGFRα(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.