线粒体基因突变糖尿病的认识、特征及临床处理

正在目前执行的分类学中,线粒体基因突变糖尿病(Mutation in mitochondrial gene diabetes mellitus,MIOD)归属于特殊类型糖尿病,β细胞功能基因缺陷、包括:MODY的几个亚型和线粒体DNA(mtDNA)所致糖尿病~([1])。至今MODY已有14个亚型~([2])。因此目前将凡是只限于一对等位基因控制而发生的遗传性糖尿病称为单基因遗传病,包     

MODY 7的研究、认识现状及处理

<正>20世纪70年代,分子生物学技术兴起,阐明了基因结构,特别是单基因突变所致者已被阐明!胰岛素基因突变、胰岛素受体基因突变、线粒体DNA基因突变、少年起病的成人型糖尿病(MODY)、新生儿糖尿病等。从此使人们不断的深入的认识了MODY,并发现他们有若干亚型,1998年Hattersley等为深入认识MODY,提出了在英国,法国遗传研     

神经分化因子-1基因与糖尿病

神经分化因子-1(NeuroD1/Beta2)基因在胰腺组织发育过程的网络调节中起着重要的作用,近年发现NeuroD1/Beta2基因突变与青幼年发病型成人糖尿病(MODY)有关。NeuroD1/Beta2是MODY6的致病基因,另据研究发现NeuroD1/Beta2基因Ala45Thr多态可能和1型糖尿病的发生相关联。本文对NeuroD1/Beta2基因突变在各种族MODY人群中筛查的研究现状及各研究组对NeuroD1/Beta2基因Ala45Thr多态和1型糖尿病发生关系的研究结果作一综述。     

MODY的分子机制和临床研究进展

年轻起病成人型糖尿病(MODY)是一种常染色体显性遗传的单基因遗传病,主要是由于β细胞功能障碍所致。目前研究所知MODY至少由6个不同的基因突变引起,即肝细胞核因子(HNF)-4α/MODY1、葡萄糖激酶/MODY2、HNF-1α/MODY3、胰岛素启动因子-1(IPF-1)/MODY4、HNF-1β/MODY5及神经源性分化因子(β细胞E框反式激活物)/MODY6。本文阐述了各型MODY的分子机制和临床特征。     

MODY的分子机制和临床研究进展

年轻起病成人型糖尿病(MODY)是一种常染色体显性遗传的单基因遗传病，主要是由于β细胞功能障碍所致。目前研究所知MODY至少由6个不同的基因突变引起，即肝细胞核因子(HNF)-4α／MODYl、葡萄糖激酶／MODY2、HNF-lα/MODY3、胰岛素启动因子-1(IPF-1)／MODY4、HNF-1β／MODY5及神经源性分化因子(β细胞E框反式激活物)／MODY6。本文阐述了各型MODY的分子机制和临床特征。     

MODY及其相关基因的研究进展

年轻的成年发病型糖尿病 (MODY)是一种常染色体显性遗传的单基因遗传病 ,它的发生与一定的基因突变相关联。目前已发现至少 6种MODY相关基因 ,即肝细胞核因子 4α(HNF 4α) /MODY1 ,葡萄糖激酶 (GCK) /MODY2、肝细胞核因子 1α(HNF 1α) /MODY3、胰岛素启动因子 1 (IPF 1 ) /MODY4、肝细胞核因子 1 β(HNF 1 β) /MODY5及MODY6/(BetaA2 /NEUROD1 ) ,后 5种基因均与胰岛素基因的转录调控有关。     

一个葡萄糖激酶基因Gly162Asp错义突变致青少年发病的成年型糖尿病2型家系报告

目的对一个高度怀疑青少年发病的成年型糖尿病2型(MODY2),即葡萄糖激酶(GCK)基因突变所致MODY家系寻找基因突变位点,并探讨其临床特点。方法对1例意外发现血糖升高、无酮症倾向、有糖尿病家族史的10岁女孩采用芯片捕获高通量测序方法进行致病基因检测,发现其携带GCK基因突变,对其家系进行调查,收集家系成员相关临床资料并取得家系成员的外周血基因组DNA,使用Sanger测序技术对家系成员进行筛查。结果该家系的5名成员检测到GCK基因(NM_000162)第5号外显子c.485GA(p.Gly162Asp)杂合错义突变,其中有4例为糖尿病患者,1例为IGR,该突变与糖尿病和IGR共分离,在白种人群中已有报道,在中国人群中为首次发现。结论 GCK基因突变c.485GA是该MODY2家系的主要致病基因。     

神经分化因子-1基因与糖尿病

神经分化因子-1(NeuroD1／Beta2)基因在胰腺组织发育过程的网络调节中起着重要的作用，近年发现NeuroD1／Baa2基因突变与青幼年发病型成人糖尿病(MODY)有关。NeuroD1／Bern2是MODY6的致病基因，另据研究发现NeuroD1／Baa2基因Ala45Thr多态可能和1型糖尿病的发生相关联。本文对NeuroD1／Beta2基因突变在各种族MODY人群中筛查的研究现状及各研究组对NeuroD1／Beta2基因Ala45Thr多态和1型糖尿病发生关系的研究结果作一综述。     

MODY及相关基因的研究进展

年轻的成年发病型糖尿病（MODY）是一种常染色体显性遗传的单基因遗传病,它的发生与一定的基因突变相关联。目前已发现至少6种MODY相关基因,即肝细胞核因子－4α（HNF－4α）／MODY1,葡萄糖激酶（GCK）／MODY2、肝细胞核因子－1α（HNF－1α）／MODY3、胰岛素启动因子－1（IPF－1）／MODY4、肝细胞核因子－1β（HNF－1β）／MODY5及MODY6／（BetaA2/NEUROD1）,后5种基因均与胰岛素基因的转录调控有关。     

青少年起病的成人型糖尿病12型1例暨文献复习

青少年起病的成人型糖尿病(maturity-onset diabetes of the young, MODY)是一组由胰岛素分泌相关基因缺陷导致的常染色体显性遗传的单基因糖尿病。多数MODY患者由于缺乏特异性的临床表现, 临床上易被误诊为1型糖尿病或2型糖尿病, 因此需要基因检测来确诊[1]。目前已发现的MODY相关基因共14个[2], 分别对应MODY 1～14型。在这14种MODY类型中, 最常见的是MODY2, 占所有MODY患者的10%～60%[3]。MODY12是一种罕见的MODY类型, 占所有MODY类型的比例<1%[4]。该病最早于2012年由Bowman等[5]报道, 目前我国关于MODY12的报道很少[6,7,8,9,10,11], 治疗经验有限。本研究报道了一例曾误诊为1型糖尿病的MODY12病例, 旨在提高临床医生对该病的认识, 减少误诊及漏诊。     

Monogenic diabetes mellitus in youth. The MODY syndromes.

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.     

A novel nonsense mutation in GCK exon 9 co-segregates with diabetes phenotype.

Maturity-onset diabetes of the young is an autosomal dominant form of non-insulin dependent diabetes mellitus and is caused by mutations in at least six different genes. In the most common forms, i.e. MODY2 and MODY3, the glucokinase (GCK) and the hepatocyte nuclear factor (HNF)-1alpha gene is affected, respectively. We have screened the GCK gene and HNF-1alpha gene by direct sequencing in three German families with early onset type-2-diabetes, possibly MODY. Next to known polymorphisms we have identified two novel intronic insertions in GCK and a novel non-sense mutation in exon 9 (C364 X). The latter mutation has an autosomal dominant inheritance pattern. Accordingly, this novel mutation segregates with diabetes phenotype in this family.     

Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase

Summary Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterised by an early age of onset and an autosomal dominant mode of inheritance. Only a proportion of cases are due to mutations in the glucokinase gene. We have studied five Caucasian MODY families, including the first MODY family to be described, with five candidate genes implicated in regulation of insulin secretion. The affected subjects showed more marked hyperglycaemia than that found in subjects with glucokinase mutations. We assessed polymorphic markers close to the genes for glucokinase, hexokinase II, adenosine deaminase, pituitary adenylate cyclase-activating polypeptide receptor, and glucagon-like peptide-1 receptor. Linkage analysis with diabetes gave cumulative log of the odds (LOD) scores of less than -3, implying that mutations in these genes are unlikely to provide a major genetic contribution to this form of MODY.Abbreviations MODY Maturity-onset diabetes of the young - GCK glucokinase - ADA adenosine deaminase - PACAP-R pituitary adenylate cyclase-activation polypeptide receptor - HK-2 hexokinase II - GLP-1 R glucagon-like peptide-1 receptor - PCR polymerase chain reaction - STRP simple tandem repeat polymorphism - NIDDM non-insulin-dependent diabetes mellitus     

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.     

Recognition of maturity-onset diabetes of the young in China

Aims/IntroductionGiven that mutations related to maturity‐onset diabetes of the young (MODY) are rarely found in Chinese populations, we aim to characterize the mutation spectrum of MODY pedigrees.Materials and MethodsMaturity‐onset diabetes of the young candidate gene‐ or exome‐targeted capture sequencing was carried out in 76 probands from unrelated families fulfilling the clinical diagnostic criteria for MODY. MAF <0.01 in the GnomAD or ExAC database was used to filter significant variants. Sanger sequencing was then carried out to validate findings. Function prediction by SIFT, PolyPhen‐2 and PROVEAN or CADD was carried out in missense mutations.ResultsA total of 32 mutations in six genes were identified in 31 families, accounting for 40.79% of the potential MODY families. The MODY subtype detection rate was 18.42% for GCK, 15.79% for HNF1A, 2.63% for HNF4A, and 1.32% for KLF11, PAX4 and NEUROG3. Seven nonsense/frameshift mutations and four missense mutations with damaging prediction were newly identified novel mutations. The clinical features of MODY2, MODY3/1 and MODYX are similar to previous reports. Clinical phenotype of NEUROG3 p.Arg55Glufs*23 is characterized by hyperglycemia and mild intermittent abdominal pain.ConclusionsThis study adds to the emerging pattern of MODY epidemiology that the proportion of MODY explained by known pathogenic genes is higher than that previously reported, and found NEUROG3 as a new causative gene for MODY.     

Maturity‐onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus

Maturity‐onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β‐cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.