基因检测决定MODY正确诊断、分型与药靶精准治疗。80%以上中国MODY是未知MODY-X基因突变所致。Rfx6是调控胰腺发育和胰岛β细胞功能上游级层的重要转录因子，参与调节多种MODY基因转录。用二代测序（NGS）筛查56个MODY家系29个单基因糖尿病靶基因，发现与糖尿病遗传-共分离的RFX6-P660R新突变（小鼠对应P559R）。研究显示：该突变体转录活性和蛋白表达均大幅度降低（˃50%）、三维结构显著改变，严重影响功能。本项目结合前期研究结果，通过构建胰腺条件性RFX6-P559R点突变小鼠模型，研究：1）该突变对胰腺和胰岛β细胞发育、分化和功能，对胰岛素基因转录与表达的影响；2）突变导致糖尿病的信号通路及相关基因转录与表达的改变；3）Rfx6过表达对于点突变小鼠糖尿病表型的逆转、缓解作用。从分子、细胞和整体水平阐明RFX6-P559R突变导致MODY型糖尿病发生的机理。

Genetic testing determines the correct diagnosis, classification and targeting drug precise treatment of MODY. More than 80% of MODY patients in Chinese are caused by unknown MODY genes i.e. MODY-X. Rfx6 is an important transcription factor that regulates the upstream factors of pancreatic development and islet beta cell function, and is involved in the regulation of the transcription of multiple MODY genes. 29 target genes of monogenic diabetes were screened by next-generation sequencing (NGS) in 56 MODY families, and a novel mutation in RFX6 (P660R in human, corresponding to P559R in mice) was identified and co-segregated with hyperglycemia. Our research showed that the transcriptional activity and protein expression of mutant significantly reduced (˃50%), and three dimensional structure of mutant changed significantly, thus the function of mutant protein may be affected severely. In this study, based on earlier clinical genotype-phenotype studies, by using pancreas conditional Rfx6-P559R point mutation mice model, we will explore this mutation in the following aspects: 1. its effect on the development, differentiation and function of pancreas and islet beta cells, as well as the transcription and expression of insulin genes; 2. to explore the change of the transcription and expression of genes related to the pathogenic signaling pathway of Rfx6; 3. how over-expression of Rfx6 in conditional point mutant mice will reverse or relieve diabetic phenotypes. The mechanism that RFX6-P559R mutation leads to MODY will be elucidated in molecular, cellular and in vivo level.