MODY3基因在早发家族性2型糖尿病发病中的作用

目的评估MODY3（HNF-1a）基因在中国家族性早发2型糖尿病（T2DM）发病中的作用。方法收集100个早发T2DM家系,PCR扩增先证者MODY3基因的外显子和外显子/内含子拼接区,产物直接测序。对发现的SNPs进行病例对照研究。结果发现5个非编码区DNA变异IVS1-16G〉A、IVS2-23C〉T、IVS5＋9C〉G、IVS7＋7A〉G、IVS9-24C〉T,4个编码区的同义突变Leu17Leu、Gly288Gly、Thr515Thr、Leu459Leu,3个编码区的错义突变Pro379Ala、Ile27Leu、Ser487Asp,其中Pro379Ala突变在一个家系中与糖尿病共分离;Ile27Leu和Ser487Asp与糖尿病不相关。结论MODY3在中国早发家族性T2DM中患病率不超过1%,在中国家族性T2DM发病中不起主要作用。     

MODY的最新临床分型及其识别

青少年发病的成年型糖尿病(maturity-onset diabetes of the young,MODY)是2型糖尿病(DM)中的一种异质性单基因疾病,约占2型糖尿病的2%～5%,特点是常染色体显性遗传,有可能收集到几代病人,发病年龄在25岁以下,并常常在儿童和青少年中发生,有时可在中年以后才出现症状.MODY因其DM临床表现轻,一般不需用胰岛素治疗,其发病和临床经过与2型DM相似,因此长期以来将MODY归为2型DM的一个亚型.     

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1.糖尿病的病因影响其治疗(Lancet,2003,262:1275-1281) 英国的一项研究显示,年轻起病成人型糖尿病(MODY)患者对磺脲类药物的治疗反应好于2型糖尿病(T2DM)患者。在这项随机交叉研究中,18名具有肝细胞核因子(HNF)-1α突变的MODY患者及18名相匹配的T2DM患者分别服用格列本脲及二甲双胍进行治疗。结果显示,与T2DM患者相比,MODY患者对磺脲类药物的反应性高3.9倍,但对二甲双胍的反应两组类似。另外,MODY患者中接受格列本脲治疗者与接受二甲双胍治疗的患者相比,果糖胺水平下降136 mmol/L,而T2DM患者中,果糖     

青少年的成人起病型糖尿病(MODY)的研究、认识现状及处理

<正>青少年的成人起病型糖尿病(Maturityonset diabetes of the youm,MODY),已被证实为单基因遗传突变引起的糖尿病,其突变基因具有遗传异质性,属于一种非胰岛素依赖的早发型糖尿病,呈常染色体显性遗传,是单基因糖尿病中常见的一型。MODY数十年前已被人们关注在应用胰岛素以前,早     

柳暗花明又一村——2型糖尿病的遗传学研究突破将糖尿病的病因学研究引入新的时代

2006年前T2DM的遗传学研究进展是相对缓慢的，糖尿病遗传学研究的艰难程度被人们称为“遗传学家的噩梦”。上世纪90年代中期，采用了基因连锁分析的定位克隆研究策略，成功地发现了几个符合孟德尔遗传模式的糖尿病致病基因（如年轻的成人发病型糖尿病，MODY）。在此鼓舞下，遗传界掀起了定位克隆普通T2DM基因的“小高潮”。在随后的10年里，国际上对大量T2DM家系在全基因组范围内进行连锁分析（全基因组扫描），几乎在每条染色体上都见到连锁信号，但只有目前尚未定论的2号染色体上的Calpain 10被发现可能与T2DM相关，这一研究策略似乎对识别T2DM这一复杂遗传病易感基因并未奏效。     

过氧化物酶体增殖物激活受体γ基因多态性与2型糖尿病的相关性研究

目的探讨北方汉族人过氧化物酶体增殖物激活受体γ(PPARγ)基因多态性与2型糖尿病(T2DM)的相关性。方法采用病例对照研究募集40例T2DM患者作为病例组和127例无T2DM者为对照。以连接酶检测反应(LDR)技术对PPARγ基因中的13个SNPs位点进行基因分型。校正年龄、性别、吸烟、饮酒后采用非条件Logistic回归在不同遗传模式下分析各基因型与T2DM的相关性。结果 rs2972164在显性模型中与T2DM发病风险相关,CT+TT较CC能够降低T2DM发病风险(OR=0.21,95%CI:0.04~0.99,P=0.049),CT较CC有降低T2DM发病风险的趋势(OR=0.21,95%CI:0.04~1.03,P=0.050)。结论 PPARγ基因多态性可能与北方汉族人T2DM遗传易感性相关。     

早发2型糖尿病家系NeuroD1基因突变筛查与功能研究

目的 在中国人早发2型糖尿病家系先证者中筛查NeuroD1基因突变/变异,并研究其功能及携带者家系的临床表型和遗传特点.方法 用PCR-直接测序法检测85例早发、95例晚发2型糖尿病家系先证者和87名非糖尿病对照者NeuroD1基因突变/变异,比较筛查到的组间突变/变异的基因型及等位基因频率的差异.分别构建含小鼠NeuroD1(mND1)基因cDNA的野生型、突变型表达质粒载体和与人胰岛素基因启动子相连的荧光素酶报告基因质粒载体,共转染至大鼠INS-1细胞.分别检测荧光素酶活性,比较野生型、突变体蛋白对人胰岛素基因转录活性的影响.结果 在一早发先证者发现新突变S159P(T→C),它与来自父方的4例携带突变的糖尿病患者遗传上呈共分离;与野生型相比,S159P突变体导致胰岛素基因转录活性下降25%;检测到常见多态A45T(G→A),与非糖尿病组及晚发2型糖尿病组相比,早发组该变异的AA+GA基因型频率显著增加(P=0.006和P=0.014).结论 NeuroD1基因S159P突变促进该早发2型糖尿病家系的发病.A45T变异增加中国人早发2型糖尿病的易感性,或与之呈连锁不平衡,该变异可能影响中国人2型糖尿病的发病方式,即早发而不是晚发.     

MODY 14的研究、认识现状及处理

<正>2015年9月14~18日,在瑞典首都斯德哥尔摩举办的第51届EASO年会上,第9届A1bert Renold奖的获得者,发表了"深入了解单基因糖尿病患者的β细胞"为题的演讲,重点回顾性的介绍了青少年的成人起病型糖尿病(MODY)和新生儿糖尿病(NDM),这两种典型的单基因糖尿病,特别是MODY属于一种非胰岛素依赖的早发型糖尿病,已被证实为单基因遗传突变引起的常染色体显性遗传的特殊类型的糖尿病。     

2型糖尿病易感基因定位克隆研究进展

糖尿病有遗传倾向且有遗传异质性。近年病因研究之深入发现了多种由单基因突变导致胰岛 B细胞胰岛素分泌不足呈孟德尔遗传或线粒体母系遗传的糖尿病。但是 ,在糖尿病者中占很大比例的 2型糖尿病 (T2 DM)是多基因遗传的复杂病(complex disease)。复杂病是由多个易感遗传基因及环境因素共同参与且相互作用而致发病。阐明 T2 DM易感基因及其与环境因素相互作用参与发病的机制并非易事 ,但却是充分防治T2 DM的前提之一。只有在计算机及分子生物技术飞速发展的今日方有可能摸索应用重组制谱 (recombinant mapping)结合连锁不平衡制谱 (linkag…     

MODY的研究进展

青少年发病的成年型糖尿病 (MODY)是 2型糖尿病中的一种异质性单基因疾病 ,特点是常染色体显性遗传。随着基因定位克隆和候选克隆等技术的发展 ,多个 2型糖尿病的易感性特定缺陷基因及其标记位点已被阐明。讨论了肝细胞核转移因子 (HNF) 4α、葡萄糖激酶 (GCK)、HNF 1α、胰岛素启动因子 (IPF) 1的基因缺陷和有关MODY的发病机制。     

Phenotypical aspects of maturity‐onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database

Aims To analyse and compare clinical characteristics in young patients with maturity‐onset diabetes of the young (MODY) and Type 2 diabetes mellitus (T2DM). Methods We conducted an observational investigation using the DPV‐Wiss database containing clinical data on 40 757 diabetic patients < 20 years of age from Germany and Austria. Results Three hundred and thirty‐nine cases were clinically categorized as MODY (0.83%); 562 patients were diagnosed as T2DM (1.4%). In 20% of cases, the diagnosis of MODY was based on clinical findings only. Of the 272 subjects where genetic testing was available, 3% did not carry mutations in the three examined MODY genes. Glucokinase‐MODY was commoner than HNF1A‐MODY and HNF4A‐MODY. Age at diagnosis was younger in MODY patients. The body mass index of T2DM was significantly higher compared with all MODY subgroups. Macrovascular risk factors such as dyslipidaemia and hypertension were commoner in T2DM, but 23% of MODY patients had dyslipidaemia and 10% hypertension. Glycaemic control was within the therapeutic target (HbA_1c < 7.5%) in 86% of MODY and 70% of T2DM patients. Conclusions The prevalence of MODY in children and adolescents in Germany and Austria is lower than that of T2DM in this age group. Dyslipidaemia and hypertension are less frequent in MODY compared with T2DM patients, but do occur.     

Etiology of early-onset type 2 diabetes in Indians: islet autoimmunity and mutations in hepatocyte nuclear factor 1alpha and mitochondrial gene

CONTEXT: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available. OBJECTIVE: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1alpha (HNF1alpha) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology. DESIGN: This was an observational cohort study. SETTING: The setting was an outpatient diabetes clinic in a teaching hospital. PATIENTS: Ninety-six consecutive young patients with T2DM (onset, 相似文献   

Mutations of maturity-onset diabetes of the young (MODY) genes in Thais with early-onset type 2 diabetes mellitus

Objective  Six known genes responsible for maturity-onset diabetes of the young (MODY) were analysed to evaluate the prevalence of their mutations in Thai patients with MODY and early-onset type 2 diabetes.
Patients and methods  Fifty-one unrelated probands with early-onset type 2 diabetes, 21 of them fitted into classic MODY criteria, were analysed for nucleotide variations in promoters, exons, and exon–intron boundaries of six known MODY genes, including HNF-4α , GCK , HNF-1α , IPF-1 , HNF-1β , and NeuroD1/β2 , by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method followed by direct DNA sequencing. Missense mutations or mutations located in regulatory region, which were absent in 130 chromosomes of non-diabetic controls, were classified as potentially pathogenic mutations.
Results  We found that mutations of the six known MODY genes account for a small proportion of classic MODY (19%) and early-onset type 2 diabetes (10%) in Thais. Five of these mutations are novel including GCK R327H, HNF-1α P475L, HNF-1α G554fsX556, NeuroD1 –1972 G > A and NeuroD1 A322N. Mutations of IPF-1 and HNF-1β were not identified in the studied probands.
Conclusions  Mutations of the six known MODY genes may not be a major cause of MODY and early-onset type 2 diabetes in Thais. Therefore, unidentified genes await discovery in a majority of Thai patients with MODY and early-onset type 2 diabetes.     

Genetic and clinical characteristics of maturity-onset diabetes of the young

Genetic factors play an important role in various forms of diabetes mellitus (DM), but inheritance is complex and interacts with environmental factors. Although in most cases type 2 DM (T2DM) and T1DM are polygenic disorders, several monogenic forms have been identified. Among them, maturity-onset diabetes of the young (MODY) has been the most intensively investigated. MODY is a group of six different forms of monogenic diabetes, characterized by insulin secretion defects in pancreatic beta-cells, supposed to be responsible for 2-5% of all cases of diabetes. The most common are MODY2 and MODY3, caused by mutations in the genes encoding glucokinase and hepatocyte nuclear factor 1-alpha respectively. MODY2 is characterized by glucose sensing defects, leading to an increase in insulin secretion threshold. This causes lifelong sustained and mild hyperglycaemia from birth, most often in non-diabetic levels. Diagnosis is incidental in most cases. These patients are asymptomatic, seldom need treatment and rarely present chronic complications. MODY3 is characterized by a severe insulin secretion defect in response to glucose. Diagnosis is made usually in adolescence and early adulthood, often by osmotic symptoms. Hyperglycaemia is progressive, and patients frequently need treatment with oral drugs or insulin some time in their follow up. This group seems to have a marked sensitivity to sulphonylureas compared to other types of diabetes. The recognition of MODY as a monogenic disorder and a thorough understanding of its pathophysiology are important for correct diagnosis and treatment, with great impact on prognosis. Besides, the study of these forms of diabetes brings important contributions to the understanding of glucose homeostasis as a whole.     

Clinical profiling and screening for HNF4α and GCK gene mutations in Kashmiri patients with maturity-onset diabetes of the young (MODY)

AimMaturity-onset Diabetes of Young (MODY) is a monogenic form of diabetes affecting 1–5% of young (often ≤25 years) diabetic patients exhibiting an autosomal dominant mode of inheritance. Considering the significance of genetic polymorphisms in a variety of diseases, this study aimed to determine the association between HNF4α and GCK gene polymorphisms and the risk of MODY in the Kashmir community, as well as their clinical differences.MethodThe study was conducted on clinically confirmed MODY patients (n = 50), and age and gender-matched controls (25 T1DM and 25 non-diabetic) recruited from the endocrinology department of the hospital, for evaluating the HNF4α and GCK mutation. Under standard conditions, PCR-mediated amplification was done to evaluate the respective exons. Preliminary mutations were detected using restriction enzymes (BfaI and HhaI), which were then followed by sequencing of representative samples. The diabetic history, clinical and biochemical data were obtained after proper consent.ResultsOur data revealed no association of HNF4α (exon7) and GCK (exon8) gene mutation with MODY disease susceptibility in the Kashmiri population. On diagnosis, no MODY patient was given immediate insulin; instead, metformin (68%) or sulphonyl-urea (28%) and dietary changes (4%) were recommended. Later in life, 54% of MODY patients develop insulin dependency. The MODY probability was calculated to be 73.88% (±4.56). HbA1c levels were lower [7.48% (±1.64)] than in T1DM [9.17(±2.29%)].ConclusionsYoung early-onset diabetic patients were able to keep their HbA1c and blood glucose levels stable with a modified diet and metformin/sulphonyl-urea, but they may become insulin-dependent in the future, as seen in our study. As a result, prompt diagnosis and management are essential for avoiding complications. Furthermore, no HNF4α (exon7) or GCK (exon 8) mutations were found in MODY patients or T1DM/healthy non-diabetic controls.     

182个2型糖尿病家系865人调查分析

目的 建立一个可用于系统研究2型糖尿病的高发家系人群,对2型糖尿病家系的发病情况、临床及生化指标进行分析.方法 按美国糖尿病学会标准,已诊断有糖尿病家族史的糖尿病先证者进行三代家族史和血统成员的调查研究,全部非患者采血做口服葡萄糖耐量试验确认,并对新老患者用免疫学方法,系谱分析和分子生物学方法排除1型糖尿病、青少年发病的成年型糖尿病(MODY)和线粒体遗传阳性家系,最终筛选出具有2个或2个以卜2型糖尿病患者的家系182个(实际调查共865人)并进行分析.全部家系成员均检查血糖、血脂、胰岛素C肽释放试验.结果 受调查的865名成员中2型糖尿病、单纯空腹血糖受损、单纯葡萄糖耐量减退、空腹血糖受损合并葡萄糖耐量减退总患病率为59.88%,2型糖尿病患病率为45.43%.新榆出2型糖尿病患者94例,单纯空腹血糖受损者14例,单纯葡萄糖耐量减退者61例,空腹血糖受损合并葡萄糖耐量减退者27例.先证者父、母、同胞、子女的患病率明显高于普通人群.糖尿病组收缩压、舒张压、总胆固醇、低密度脂蛋白胆固醇、甘油二酯、体重指数、胰岛素抵抗指数明显高于空腹血糖受损和(或)葡萄糖耐量减退组或未发病者.在2型糖尿病发病前的葡萄糖耐量减退阶段,收缩压、舒张压、总胆固醇、低密度脂蛋白胆固醇、甘油三酯、体重指数、胰岛素抵抗指数也高于正常人群.结论 2型糖尿病发病具有明显的家族聚集性,高血压、高血脂、肥胖是2型糖尿病的高危因素,胰岛素抵抗在糖尿病发病前已存在.     

Genetics of type 2 diabetes mellitus and other specific types of diabetes; its role in treatment modalities

Type 2 diabetes mellitus (T2DM) is among the most challenging health issues of the 21st century and is associated with an alarming rise in the incidence. The pathophysiological processes that lead to development of T2DM are still unclear, however impairment in insulin secretion and/or action is clearly indicated. Type 2 diabetes is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder. Only a minority of cases of type 2 diabetes are caused by single gene defects and one example is maturity onset diabetes of the young (MODY). Previous studies indicated that variants in genes encoding the pancreatic β-cell K+ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are associated with neonatal diabetes. Six different types of maturity onset diabetes of young (MODY) have been identified based on characteristic gene defect. The common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPAR-γ) gene was confirmed in several studies to be associated with type 2 diabetes as well. More recently, studies reported variants within a novel gene, TCF7L2, as a putative susceptibility gene for type 2 diabetes across many ethnic backgrounds around the world. MODY patients respond better to sulphonylureas and metformin, while neonatal diabetes patients with genetic mutations can be changed from insulin to oral drugs. We hereby provide a comprehensive review on the role of genetics in type 2 diabetes mellitus.