Generation of gene-targetting mice with gain-of-function mutation of c-kit gene

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The c-kit gene encodes a receptor tyrosine kinase, KIT. And the ligand for KIT is stem cell factor, SCF. We found a family with multiple gastrointestinal stromal tumors (GISTs) and c-kit mutation at juxtamembrane domain. The patients had hyperplasia of interstitial cells of Cajal (ICCs) which is considered to be a precancerous lesion of GISTs. We attempted to make a mouse model of familial and multiple GISTs. Targetting vector containing genomic c-kit gene with gain-of-function mutation is making now, so the result has not been obtained. We produced transgenic mice with gain-of-function mutation of c-kit gene, and are now analyzing.We found other 3 families with multiple GISTs. Germline mutation of c-kit gene was observed in the family members. One family had a mutation at juxtamembrane domain, another at tyrosine kinase I domain, and the other at tyrosine kinase II domain. All the mutations were found to be gain-of-function types. They also had diffuse hyperplasia of ICCs. The patients with mutation at tyrosine kinase II domain complained of dysphagia that may be resulted from ICC hyperplasia at esophagogastric junction. We will also make mouse models that have tyrosine kinase I domain or tyrosine kinase II domain.