共查询到20条相似文献,搜索用时 343 毫秒
1.
Ellard S 《Human mutation》2000,16(5):377-385
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (<25 years) and pancreatic beta-cell dysfunction. MODY is genetically heterogeneous with five different genes identified to date: 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]. Mutations in the HNF-1 alpha gene represent a common cause of MODY in the majority of populations studied. Sixty-five different mutations have been described in a total of 116 families. The most common mutation is a C-insertion (P291fsinsC) in the polyC tract of exon 4, which has been reported in 22 families. The identification of an HNF-1 alpha gene mutation in a patient with type 2 diabetes confirms the diagnosis of MODY and has important implications for clinical management. 相似文献
2.
Diabetes mellitus 总被引:10,自引:0,他引:10
Iwasaki N 《Rinsho byori. The Japanese journal of clinical pathology》2001,49(2):161-164
Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes. 相似文献
3.
4.
Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1alpha) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty-three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG-->CCA) and a 6bp intronic deletion of the HNF-1alpha gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi-palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop. 相似文献
5.
6.
7.
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often <25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), hepatocyte nuclear factor-1 alpha (HNF1A, or TCF1), hepatocyte nuclear factor-4 alpha (HNF4A), insulin promoter factor-1 (IPF1 or PDX1), hepatocyte nuclear factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNF1A gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management. 相似文献
8.
Kevin Colclough Christine Bellanne‐Chantelot Cecile Saint‐Martin Sarah E. Flanagan Sian Ellard 《Human mutation》2013,34(5):669-685
Maturity‐onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young‐onset (typically <25 years), noninsulin‐dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor‐1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor‐4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ~50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost‐effective gene analysis for all patients with young onset diabetes. 相似文献
9.
Guazzini B Gaffi D Mainieri D Multari G Cordera R Bertolini S Pozza G Meschi F Barbetti F 《Human mutation》1998,12(2):136
The maturity-onset diabetes of the young (MODY), an autosomal dominant form of non-insulin dependent diabetes mellitus (NIDDM), is caused by mutations in the glucokinase (GK, MODY 2) and in the hepatocyte nuclear factor 1a (MODY 3) and 4a (MODY 1) genes. We have screened the glucokinase gene by the polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) in fifteen subjects with clinical characteristics of MODY and one parent with NIDDM, impaired glucose tolerance or gestational diabetes. PCR products with abnormal mobility in DGGE were directly sequenced. We have identified four mutant alleles, three of them (G80S, E221K, G227C) are new missense mutations located in or near the region of the active site cleft of the enzyme. The mutations co-segregate with hyperglycemia in the families of the three probands, whose biochemical and clinical phenotype is similar to other individuals with MODY 2 mutations. 相似文献
10.
Sian Ellard Michael P. Bulman Timothy M. Frayling Maggie Shepherd Andrew T. Hattersley 《Human mutation》2000,16(3):273-273
Maturity‐onset diabetes of the young (MODY) is a monogenic subgroup of non‐insulin dependent diabetes (NIDDM) characterized by an early age of diagnosis (usually < 25 years) and an autosomal dominant mode of inheritance. Mutations in the hepatocyte nuclear factor 1 alpha (HNF‐1α) [MODY3] gene represent the most common cause of MODY in the UK and a common cause of MODY in many other populations. Sixty‐three different mutations have been described in a total of 112 families worldwide. This report describes two families, not known to be related, who carry a novel insertion/deletion mutation (I414G415ATCG→CCA) and a 6bp intronic deletion of the HNF‐1α gene in cis. We propose that the insertion/deletion mutation has arisen by formation of a hairpin loop due to the presence of a quasi‐palindromic sequence, followed by insertion of CC and deletion of TCG resulting in the increased stability of the hairpin loop. Hum Mutat 16:273, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
11.
A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young 总被引:9,自引:0,他引:9
Thomas H Jaschkowitz K Bulman M Frayling TM Mitchell SM Roosen S Lingott-Frieg A Tack CJ Ellard S Ryffel GU Hattersley AT 《Human molecular genetics》2001,10(19):2089-2097
12.
T H Lindner P R Njolstad Y Horikawa L Bostad G I Bell O Sovik 《Human molecular genetics》1999,8(11):2001-2008
13.
Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients 总被引:6,自引:0,他引:6
Xu JY Dan QH Chan V Wat NM Tam S Tiu SC Lee KF Siu SC Tsang MW Fung LM Chan KW Lam KS 《European journal of human genetics : EJHG》2005,13(4):422-427
In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance. 相似文献
14.
中国人早发及多发糖尿病家系HNF-1α基因突变的筛查 总被引:6,自引:2,他引:6
目的 了解中国人早发及多发糖尿病家系中肝细胞核因子HNF 1α基因突变发生情况。方法 应用聚合酶链反应 单链构象多态性技术和测序方法对 2 47名无亲缘关系上海地区中国人 [其中 93名为正常对照者 ,15 4例为早发和 (或 )多发糖尿病家系先证者 ]进行HNF 1α基因启动子区、10个外显子及其侧翼内含子区筛查。结果 在 15 4例糖尿病家系先证者者中见到 14种碱基改变。 3种改变未见于 93名非糖尿病者 ,其中启动子区nt -12 8T→G和IVS2nt 2 1G→A未见报道 ,且在家系中表现为与糖尿病共分离 ;另 11种碱基改变 ,它们的基因型和等位基因频率在糖尿病者及非糖尿病者间差异未见显著性 ,且各变异与血糖、胰岛素、C 肽及空腹血脂谱等临床变量均无相关。结论 HNF 1α基因突变不是上海地区中国人早发及多发糖尿病的主要原因。 相似文献
15.
16.
17.
18.
19.
Laura del Bosque-Plata Eduardo García-García Salvador Ramírez-Jimnez Javier Cabello-Villegas Laura Riba Amir Gmez-Len Gerardo Vega-Hernndez Nelly Altamirano-Bustamante Raul Calzada-Len Carlos Robles-Valds Fernando Mendoza-Morfín Oliva Curiel-Prez M. Teresa Tusi-Luna 《American journal of medical genetics. Part A》1997,72(4):387-393
Non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, affecting 5% of the general population. Genetic factors play an important role in the development of the disease. While in other populations NIDDM is usually diagnosed after the fifth decade of life, in Mexico a large proportion of patients develop the disease at an early age (between the third and the fourth decade). In Caucasian population, mutations in the glucokinase gene, the TCF1, and TCF14 genes, have been identified in a subgroup of early-onset NIDDM patients denominated MODY (maturity-onset diabetes of the young), which show an autosomal dominant pattern of inheritance. As a first step in the molecular characterization of Mexican families displaying early-onset NIDDM we searched for mutations in the glucokinase gene through SSCP analysis and/or direct sequencing in 26 individuals from 22 independent families, where at least four can be classified as MODY. No mutations were detected in the exons or the intron-exon boundaries of the gene in any of the screened individuals. The phenotype and clinical profile of some of the studied patients is compatible with that of patients carrying mutations in the TCF1 or TCF14 genes, while others may carry mutations in different loci. Through computer simulation analysis we identified at least four informative families which will be used for further linkage studies. Am. J. Med. Genet. 72:387–393, 1997. © 1997 Wiley-Liss, Inc. 相似文献
20.
Variants in hepatocyte nuclear factor 4A (HNF4A) cause maturity onset diabetes of the young (MODY 1). The objective of the study was to screen the coding and the promoter regions of HNF4A mutations in 87 unrelated South Indian subjects with clinically diagnosed MODY with severe forms of diabetes referred to a tertiary diabetes centre. In addition, we looked at the association of common polymorphisms in HNF4 A gene in subjects with MODY (n = 199), early onset type 2 diabetes (T2DM) (n = 505), late onset T2DM (n = 287) and normal glucose tolerance (NGT) (n = 247). We identified three novel mutations in the P2 promoter region of HNF4A, namely -1009 G/C, -129 T/C and -79 C/T. Co-segregation with diabetes was noted with the -1009 G/C and -129 T/C in one MODY family. We also studied eight single nucleotide polymorphisms (SNPs) of HNF4A gene. The frequency of the minor allele of the rs2144908 was significantly higher in subjects with MODY (p < 0.01) and that of rs736823 was significantly higher in early onset T2DM (p = 0.001). Minor allele frequency of rs1884614 and rs2071197 was significantly lower in early onset T2DM when compared to NGT subjects (p < 0.01). Minor allele frequency of Val255Met was significantly lower in MODY, early onset T2DM and late onset T2DM compared to NGT subjects (p < 0.01). This is the first report of MODY 1 mutations from India and shows that 3.4% of clinically diagnosed MODY subjects have MODY 1. In addition, we report SNPs of HNF4A that are both susceptible to, and protective against, MODY and early onset T2DM. 相似文献