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

c-kit基因编码酪氨酸激酶受体KIT。KIT的配体是干细胞因子，SCF。我们发现了一个具有多发性胃肠道间质瘤（gist）和近膜结构域c-kit突变的家族。患者有Cajal间质细胞（ICCs）增生，被认为是gist的癌前病变。我们尝试建立家族性和多发性胃肠道间质瘤小鼠模型。目前正在制作含有功能获得性突变的基因组c-kit基因的靶载体，因此尚未获得结果。我们培育了c-kit基因功能获得突变的转基因小鼠，目前正在进行分析。我们发现另外3个家庭有多发性胃肠道间质瘤。c-kit基因在家族成员中发生种系突变。一个家族在近膜结构域突变，另一个家族在酪氨酸激酶I结构域突变，另一个家族在酪氨酸激酶II结构域突变。所有突变均为功能获得型。他们也有ICCs弥漫性增生。酪氨酸激酶II结构域突变的患者主诉吞咽困难，这可能是由食管胃交界处ICC增生引起的。我们还将制作具有酪氨酸激酶I结构域或酪氨酸激酶II结构域的小鼠模型。

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.