miR1470对青少年起病的成年型糖尿病3（MODY3）基因表观调控的机制研究及临床意义

Maturity onset diabetes of the young (MODY) is a group of monogentic diabetes with high genetic and clinical heterogeneity. In Chinese population, the underlying genetic mutations and pathogenesis of 90% to 95% MODY are still unknown. In our previous study, we identified a novel heterozygous point mutation c.2116G>T in the 3' UTR region of the HNF1a gene in a pedigree of early onset type 2 diabetes. The mutation was cosegregated with diabetes in this pedigree. Bioinformatic analysis predicted the mutation to be located in the target site of miR-1470 on the HNF1a gene. We hypothesize that the c.2116G>T mutation disrupts the binding of miR-1470 with its target HNF1a, thus increases the expression of HNF1a and leads to diabetes in patients. In the present study, we will explore the mechanism by which miR-1470 epigenetically regulates HNF1a expression using cell culture and an animal model. Meanwhile, with the population study, we will explore the clinical implication of miR-1470 and the c.2116G>T mutation in early-onset hereditary type 2 diabetes. With these efforts, we hope to provide new clues for the etiology of MODY and theoretical basis for personalized therapy.

青少年起病的成年型糖尿病(MODY)是一组具有高度遗传性和临床异质性的单基因突变糖尿病, 在中国人群中，90％～95％MODY致病基因或致病位点仍不明确。MODY3是HNF1a基因突变导致的糖尿病类型,前期我们在一个早发2型糖尿病家系中发现了HNF1a基因3’非翻译区一个全新的单碱基杂合突变c.2116G>T，家系中突变与糖尿病表型共分离，并预测到突变位点位于miR-1470作用靶位点上。我们推测c.2116G>T突变干扰了miR-1470对HNF1a的调控作用，从而导致HNF1a表达上调及糖尿病风险上升。本课题将从细胞层面和动物在体水平阐述miR-1470对HNF1a基因的表观遗传调控机制，并结合临床，探讨HNF1a非翻译区c.2116G>T突变和miR-1470表观调控机制对早发遗传性2型糖尿病临床意义。本课题可以为MODY及部分早发2型糖尿病的发病机制研究提供新的思路。

青少年起病的成年型糖尿病(MODY)是一组具有高度遗传性和临床异质性的单基因突变糖病, 在中国人群中，90％～95％MODY致病基因或致病位点仍不明确。MODY3是HNF1a基因突变导致的糖尿病类型, 前期我们在一个早发2型糖尿病家系中发现了HNF1a基因3’非翻译区一个全新单碱基杂合突变c.2116G>T，在215名早发2型糖尿病患者中，GG型的检出率为59.5%，GT型为24.2%，TT型为16.5%。年龄、男女患者比例、BMI、血压、血脂、HbA1c以及HOMA-IR水平在3个不同基因型的组间并无显著差异，在不同癌组织样本及癌旁组织中，miR1470在肝癌组织中表达丰度最高，荧光素酶报告基因系统体外分析提示hnf1a作为miR1470的下游靶基因，下调miR-1470会引起HNF1α表达上调，引起GLUT2蛋白表达下降，导致糖代谢紊乱，流式细胞分析显示miR-1470还与细胞的增殖和凋亡相关。此外课题组确诊了新生儿糖尿病及MODY2家系，分别在INS基因第2个外显子中发现杂合突变L35Q，GCK基因第四外显子杂合突变376A deletion,上述突变目前尚未报导。本课题有希望为MODY及部分早发遗传性2型糖尿病的发病机制研究开拓新的思路。

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