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

点击翻译按钮获取中文摘要

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.