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

C-kit基因编码一种受体酪氨酸激酶，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c-kit基因突变的家系。患者有Cajal间质细胞增生(ICCs)，被认为是GIST的癌前病变。我们试图建立一种家族性和多发性GIST小鼠模型。含有c-kit基因功能获得突变的靶向载体目前正在制作中，尚未得到结果。我们培育出了c-kit基因功能获得突变的转基因小鼠，目前正在进行分析。我们还发现了另外3个具有多个GIST的家系。在家系成员中观察到c-kit基因的胚系突变。一个家系在膜旁区域发生突变，另一个家系在酪氨酸激酶I区域发生突变，另一个家系在酪氨酸激酶II区域发生突变。所有突变均为功能获得型。ICCs弥漫性增生。酪氨酸激酶II区突变的患者以吞咽困难为主诉，这可能是由于食管胃交界处ICC的增生所致。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.