种族间MODY基因谱差异极大，中国人MODY90%以上系未知MODY（MODY-X)基因突变所致。 Foxa2是调控胰腺发育、胰岛β细胞功能、糖脂代谢信号通路和胰岛素敏感性的重要转录因子，参与调节MODY基因转录。我们对MODY-X家系筛查Foxa2基因，发现与糖尿病呈遗传共分离的新突变G92S家系。研究显示，与野生型相比，G92S蛋白导致SUR1转录活性上升78.7%；结构预测显示，G92S突变导致Foxa2蛋白结构高度不稳定，严重影响其功能。本项目我们结合前期研究结果，通过Foxa2-G92S突变基因敲入小鼠模型，研究G92S突变：1）对于胰腺发育、胰岛β细胞功能的影响；2）对于糖、脂代谢的不同信号通路基因表达以及胰岛素敏感性的影响；3）基因敲入小鼠中Foxa2过表达对于糖尿病表型的逆转、缓解作用。为阐明G92S参与MODY糖代谢调控分子机理及基因制药靶点,提供精准医学的重要依据。

MODY gene spectrum varies remarkably among different races. 90% of MODY patients in China are caused by unknown MODY genes i.e. MODY-X. Foxa2, an important transcription factor, regulates pancreatic development, the function of islet β-cell, the signaling pathways of glycolipid metabolism as well as insulin sensitivity, and it controls the transcription of MODY genes. By screening genetic mutations of Foxa2 gene in MODY-X families, we found a G92S mutation which genetically co-segregated with diabetes. Functional study showed that the SUR1 transcription activity of G92S mutant protein increased by 78.7% than that of wild type. Structural prediction indicated that G92S mutation resulted in a high degree of instability of Foxa2 protein structure, suggesting this mutation has severely influenced function of Foxa2. In this study, combining with earlier clinical phenotype studies, by using Foxa2 G92S mutation gene knock-in mouse model, we will explore G92S mutation in the following aspects: 1. its effects on the development of pancreas and the function of islet β-cell; 2. how it affects the expression of different genes regarding to the signaling pathways of glycolipid metabolism and insulin sensitivity; 3. how over-expression of Foxa2 in gene knock-in mice will reverse or relieve diabetic phenotypes. In this way, we could provide significant evidence in precision medicine and insights of molecular mechanisms through which G92S mutation involves in regulation of glycometabolism and targets of gene therapy.