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Elucidation of pathogenic mechanism of diabetes associated with the abnormal HNF gene

阐明HNF基因异常相关的糖尿病发病机制

基本信息

批准号：
10470230
负责人：
HANAFUSA Toshiaki
金额：
$ 6.08万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470230/
关键词：
MODY HNF type 1 diabetes type 2 diabetes PCR direct sequence insulin gene transgenic mouse promoter 発症機序遺伝子 PCR直接シークエンス haploinsufficiency dominant negative gain of function

项目摘要

Maturity-onest diabetes of the young (MODY) due to the abnormal HNF gene is the most frequent type of diabetes caused by monogenic abnormality. We studied the possibility that the abnormal HNF gene could also cause type 1-or type 2-like diabetes other than MODY.We screened 46 patients with type 1 diabetes and 52 patients with type 2 diabetes, including 10 patients with MODY. We studied HNF-1α, HNF-1β and HNF-4α genes for possible mutations using PCR direct sequencing method. As a result, we found four mutation in the HNF-1α gene (G415R, R272C, A site, E48fsdelG) in 4 patients (3 typ 1 and MODY patients). Mutant HNF-1α containing these mutations induced a decrease in the transcription activity of the insulin gene. This suggests that decrease in the expression of the insulin gene could result in the development of diabetes. As for the HNF-1b gene, we identified one mutation (S36F) in on MODY patient. In a collaborative study with Professor Takeda (Gunma University), we cloned the human HNF-3β cDNA and its gene. Analysis of the HNF-3β gene in 80 type 2 diabetic patients revealed one missense mutation (A86T) in one patient.Transgenic mice expressing the mutant HNF-1α gene in pancreatic beta cells developed diabetes, establishing in vivo the concept that the abnormal HNF gene could result in diabetes.

青年成熟型糖尿病(MODY)是由单基因异常引起的最常见的糖尿病类型。我们研究了除MODY外，HNF基因异常也可引起1型或2型糖尿病的可能性。我们筛查了46名1型糖尿病患者和52名2型糖尿病患者，其中包括10名MODY患者。我们采用聚合酶链式反应直接测序法对hnf-1α、hnf-1β和hnf-4α基因进行了突变检测。因此，我们在4例患者中发现了4个α基因突变(G415R、R272C、A位、E48fsdelG)。含有这些突变的突变型hnf-1α导致胰岛素基因转录活性下降。这表明胰岛素基因的表达减少可能导致糖尿病的发生。至于HNF-1b基因，我们在MODY患者中发现了一个突变(S36F)。在与群马大学武田教授的合作研究中，我们克隆了人hnf-3β及其基因。对80例2型糖尿病患者的hnf-3β基因分析发现，1例患者存在1个错义突变(A86T)。在胰岛β细胞中表达突变hnf-1α基因的转基因小鼠发生糖尿病，在体内确立了异常hnf基因可能导致糖尿病的概念。