转录因子HNF1α基因c.493T>C位点突变对其蛋白质水平的影响  

Effect of mutation at c.493T>C locus of transcription factor HNF1α gene on its protein level

作　　者：梁淑杰 彭乙华[2] 雷佳红[3] 贾艾敏[3] 蒋红[3] 蔡燕[1,3,4,5] Shujie Liang;Yihua Peng;Jiahong Lei;Aimin Jia;Hong Jiang;Yan Cai(Genetic and Prenatal Diagnosis Center,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,China;Department of Endocrinology,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,China;Institute of Rheumatoid Immunology,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,China;School of Laboratory Medicine,North Sichuan Medical College,Nanchong 637000,China;Translational Medicine Research Center,North Sichuan Medical College,Nanchong 637000,China)

机构地区：[1]川北医学院附属医院遗传与产前诊断中心,南充637000 [2]川北医学院附属医院内分泌科,南充637000 [3]川北医学院附属医院风湿免疫研究所,南充637000 [4]川北医学院检验医学院,南充637000 [5]川北医学院转化医学研究中心,南充637000

出　　处：《遗传》2024年第3期256-262,共7页Hereditas（Beijing)

基　　金：川北医学院附属医院第一批临床研究课题(编号:2021LC009);川北医学院博士启动基金项目(自然科学类)(编号:CBY22-QDA28)资助。

摘　　要：肝细胞核因子1α(hepatocyte nuclear factor 1α,HNF1α)作为一种转录因子在维持胰腺β细胞功能、肝脏脂质代谢等过程中发挥着重要的调控作用。该基因突变是导致青少年起病的成人型糖尿病(maturity onset diabetes of the young,MODY)3型的致病原因,目前已报道的该基因的突变位点众多,如P291fsinsC、P112L等常见的突变位点,但其具体的分子机制尚不清楚。本研究对前期工作中发现的1例携带有HNF1α基因c.493T>C位点突变的MODY3患者,通过应用Mutation Surveyor软件分析突变位点的致病性,构建HNF1α野生型和突变型真核表达质粒,采用Western blot检测两种质粒表达的HNF1α蛋白质的量和稳定性变化,结果发现Mutation Surveyor软件分析提示c.493T>C位点突变可能为致病性变异基因,Western blot显示突变型真核质粒表达的HNF1α蛋白质的量和稳定性均明显降低,差异均具有统计学意义(P<0.05)。上述结果表明c.493T>C(p.Trp165Arg)变异显著影响HNF1α的表达量及稳定性,可能为其导致疾病发生的原因,为后续深入探究MODY3的分子致病机制提供了新的方向。Hepatocyte nuclear factor 1α(HNF1α)is a transcription factor that is crucial for the regulation to maintain the function of pancreaticβ-cell,hepatic lipid metabolism,and other processes.Mature-onset diabetes of the young type 3 is a monogenic form of diabetes caused by HNF1αmutations.Although several mutation sites have been reported,the specific mechanisms remain unclear,such hot-spot mutation as the P291fsinsC mutation and the P112L mutation and so on.In preliminary studies,we discovered one MODY3 patient carrying a mutation at the c.493T>C locus of the HNF1αgene.In this study,we analyzed the pathogenic of the mutation sites by using the Mutation Surveyor software and constructed the eukaryotic expression plasmids of the wild-type and mutant type of HNF1αto detect variations in the expression levels and stability of HNF1αprotein by using Western blot.The analyses of the Mutation Surveyor software showed that the c.493T>C site mutation may be pathogenic gene and the results of Western blot showed that both the amount and stability of HNF1αprotein expressed by the mutation type plasmid were reduced significantly compared to those by the wild type plasmid(P<0.05).This study suggests that the c.493T>C(p.Trp165Arg)mutation dramatically impacts HNF1αexpression,which might be responsible for the development of the disease and offers fresh perspectives for the following in-depth exploration of MODY3's molecular pathogenic process.

关 键 词：MODY HNF1α 基因突变 

分 类 号：R587.1[医药卫生—内分泌]