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

具有c-kit基因功能获得性突变的基因靶向小鼠的产生

基本信息

批准号：
12670203
负责人：
HIROTA Seiichi
金额：
$ 2.62万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670203/
关键词：
c-kit gene geymline mutation GIST ICCs gene-targetting transgenic mice c-kit遺伝子 ICCS カハールの介在細胞

项目摘要

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.

c-kit 基因编码受体酪氨酸激酶 KIT。 KIT的配体是干细胞因子SCF。我们发现一个家族患有多发性胃肠道间质瘤 (GIST) 且近膜域存在 c-kit 突变。患者存在卡哈尔间质细胞（ICC）增生，被认为是胃肠道间质瘤的癌前病变。我们尝试制作家族性和多发性胃肠道间质瘤的小鼠模型。目前正在制作含有功能获得性突变的基因组c-kit基因的靶向载体，因此尚未获得结果。我们培育了带有c-kit基因功能获得性突变的转基因小鼠，现在正在进行分析。我们发现了其他3个家族患有多发性GIST。家族成员中观察到c-kit基因种系突变。一个家族在近膜结构域发生突变，另一个家族在酪氨酸激酶 I 结构域发生突变，另一个家族在酪氨酸激酶 II 结构域发生突变。发现所有突变都是功能获得型。他们还患有弥漫性 ICC 增生。酪氨酸激酶II结构域突变的患者主诉吞咽困难，可能是食管胃交界处ICC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。