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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CREB-binding protein (CBP) and CBP-associated factor (P/CAF) are coactivators possessing an intrinsic histone acetyltransferase (HAT) activity. They are positioned at promoter regions via association with sequence-specific DNA-binding factors and stimulate transcription in a gene-specific manner. The current view suggests that coactivator function depends mainly on the strength and specificity of transcription factor-coactivator interactions. Here we show that two dominant-negative mutants of hepatocyte nuclear factor-1alpha (HNF-1alpha), P447L and P519L, occurring in maturity onset diabetes of the young (MODY3) patients, exhibit paradoxically stronger interactions than the wild-type protein with either CBP or P/CAF. However, CBP and P/CAF recruited by these mutants lack HAT activity. In contrast, wild-type HNF-1alpha and other transcription factors, such as Sp1 or HNF-4, stimulated the HAT activity of CBP. The results suggest a more dynamic role for DNA-binding proteins in the transcription process than was considered previously. They are not only required for the recruitment of coactivators to the promoter but they may also modulate their enzymatic activity.
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PMID:Transcription factor-dependent regulation of CBP and P/CAF histone acetyltransferase activity. 1129 31

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.
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PMID:[Diabetes mellitus]. 1130 9

Maturity-onset diabetes of the young (MODY) exhibits an autosomal dominant pattern of inheritance and can be divided in at least five subtypes (MODY 1 to 5), each subtype being caused by mutations in a specific gene. The unambiguous molecular diagnosis of the specific MODY subtype facilitates an early diagnosis of diabetes and can help to reduce the development of diabetic complications. Furthermore, MODY2 patients generally have a milder clinical course and fewer complications than MODY3 patients, who consequently require a more aggressive therapeutic approach.
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PMID:[From gene to disease; 'maturity-onset diabetes of the young' (MODY), monogenetic inheritable forms of diabetes mellitus]. 1148 33

Maturity-onset diabetes of the young (MODY), an autosomal dominant, early-onset form of type-2 diabetes, is caused by mutations in five different genes all leading to defect(s) in the pancreatic beta cell. However, some patients with this form of diabetes do not bear a mutation in any of the known (MODY1-MODY5) loci, a notion prompting the search for new MODY genes. Clinical and genetic data point toward a defect in beta cell function in the majority of patients with MODY, and partners of the glucose-sensing device are reasonable functional candidates. The high-capacity glucose transporter GLUT2 has the ideal kinetic features for performing this task. However, complete GLUT2 deficiency in humans leads to hepato-renal glycogenosis (Fanconi-Bickel syndrome), and heterozygous GLUT2 mutations apparently behave in a recessive manner. Furthermore, in the human beta cell GLUT1 mRNA is predominant when compared to GLUT2 and glucose influx appears to be largely mediated by this low-Km transporter. Thus, we looked for the presence of sequence variants by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) within the GLUT1 gene in 90 Italian pedigrees negative at the search for mutations in glucokinase (MODY2) and hepatocyte nuclear factor-1alpha (MODY3), the two genes responsible for about 60% of MODY cases in Italian children. We found three already described silent mutations and a new single base deletion in position -173 of the 5' regulatory region. The -173de1A variant, which was detected in the heterozygous or homozygous state in 30.8% of MODY patients examined and is located in a Nuclear Factor Y binding sequence, is not associated with hyperglycemia in affected relatives of MODY probands. In conclusion, it appears from these results that the glucose transporter gene GLUT1 is unlikely to play a major role in the etiology of MODY diabetes.
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PMID:Single-strand conformation polymorphism analysis of the glucose transporter gene GLUT1 in maturity-onset diabetes of the young. 1148 13

Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.
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PMID:A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. 1159 Jan 26

Recently, several genes associated with early-onset, autosomal dominant Type 2 diabetes (MODY) have been identified. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene seem to account for a substantial proportion of this type of diabetes in several populations. However, it is still of interest to estimate the frequency of HNF-1alpha mutations in various ethnic groups. The aim of our study was to determine the contribution of the HNF-1alpha gene to the development of MODY in a Polish population. We selected 15 families with MODY for this project. The 10 exons and promoter region of the gene were screened for sequence differences by direct sequencing of probands DNA. We detected 7 previously described polymorphisms that were not associated with diabetes. However, one sequence difference, a deletion of a cytosine in codon 225 in exon 3 (designated S225fdelC), was a new mutation resulting in a frame shift and synthesis of a nonsense peptide from amino acid 225 to 232 followed by the stop codon. Thus, the S225fdelC mutation effectively caused the loss of a part of the DNA binding domain and the entire transactivation domain. This mutation was present in 4 affected members of the family. They developed diabetes at an early age (mean age at diagnosis 23 yr) and were characterized by severely impaired insulin secretion. In addition, one family member who was not a carrier of the S225fdelC mutation was diagnosed with diabetes. Thus, he represents an example of phenocopy. In conclusion, we have identified a new HNF-1alpha variant that represents the first MODY mutation described in a Polish population. MODY3 mutations, including those in the exon 4 "hot spot", do not appear to be a very common cause of MODY in the Polish population.
Diabetes Nutr Metab 2001 Oct
PMID:Identification of a new mutation in the hepatocyte nuclear factor-1alpha gene in a Polish family with early-onset type 2 diabetes mellitus. 1180 70

In an attempt to identify novel susceptibility genes predisposing to early-onset diabetes (EOD), we performed a genome-wide scan using 433 markers in 222 individuals (119 with diabetes) from 29 Scandinavian families with > or =2 members with onset of diabetes < or =45 years. The highest nonparametric linkage (NPL) score, 2.7 (P < 0.01), was observed on chromosome 1p (D1S473/D1S438). Six other regions on chromosomes 3p, 7q, 11q, 18q, 20q, and 21q showed a nominal P value <0.05. Of the EOD subjects in these 29 families, 20% were GAD antibody positive and 68% displayed type 1 diabetes HLA risk alleles (DQB*02 or 0302). Mutations in maturity-onset diabetes of the young (MODY) 1-5 genes and the A3243G mitochondrial DNA mutation were detected by single-strand conformation polymorphism and direct sequencing. To increase homogeneity, we analyzed a subsample of five families with autosomal dominant inheritance of EOD (greater than or equal to two members with age at diagnosis < or =35 years). The highest NPL scores were found on chromosome 1p (D1S438-D1S1665; NPL 3.0; P < 0.01) and 16q (D16S419; NPL 2.9; P < 0.01). After exclusion of three families with MODY1, MODY3, and mitochondrial mutations, the highest NPL scores were observed on chromosomes 1p (D1S438; NPL 2.6; P < 0.01), 3p (D3S1620; NPL 2.2; P < 0.03), 5q (D5S1465; NPL 2.1; P < 0.03), 7q (D7S820; NPL 2.0; P < 0.03), 18q (D18S535; NPL 1.9; P < 0.04), 20q (D20S195; NPL 2.5; P < 0.02), and 21q (D21S1446; NPL 2.2; P < 0.03). We conclude that considerable heterogeneity exists in Scandinavian subjects with EOD; 24% had MODY or maternally inherited diabetes and deafness, and approximately 60% were GAD antibody positive or had type 1 diabetes-associated HLA genotypes. Our data also point at putative chromosomal regions, which could harbor novel genes that contribute to EOD.
Diabetes 2002 May
PMID:Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. 1197 63

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 diabetes characterised by an early onset, an autosomal dominant inheritance, and a primary defect in insulin secretion. MODY comprises 2-5% of cases of type 2 diabetes. So far, six MODY genes have been identified (MODY1-6): hepatocyte nuclear factor (HNF-4 alpha), glucokinase, HNF-1 alpha, HNF-1 beta, insulin promoter factor 1(IPF-1), and neurogenic differentiation factor 1 (NEUROD1). MODY2 and MODY3 are the most common forms of MODY. Mutations in glucokinase/MODY2 result in a mild form of diabetes. In contrast, MODY3 and some of the other MODY forms are characterised by major insulin secretory defects and severe hyperglycaemia associated with microvascular complications. About 25% of known MODY is caused by mutations in yet unknown genes and present results suggest that other monogenic forms of type 2 diabetes might exist. The diagnosis of MODY has implications for the clinical management of the patient's diabetes. The identification of MODY genes also opens new perspectives in the understanding of the molecular basis of diabetes and may probably contribute to the definition of novel targets for drug development and gene therapy.
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PMID:[Maturity-onset diabetes of the young--MODY. Molecular-genetic, pathophysiological and clinical characteristics]. 1198 98

The bifunctional protein DCoH (Dimerizing Cofactor for HNF1) acts as an enzyme in intermediary metabolism and as a binding partner of the HNF1 family of transcriptional activators. HNF1 proteins direct the expression of a variety of genes in the liver, kidney, pancreas, and gut and are critical to the regulation of glucose homeostasis. Mutations of the HNF1alpha gene underlie maturity onset diabetes of the young (MODY3) in humans. DCoH acts as a cofactor for HNF1 that stabilizes the dimeric HNF1 complex. DCoH also catalyzes the recycling of tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases. To examine the roles of DCoH, a targeted deletion allele of the murine DCoH gene was created. Mice lacking DCoH are viable and fertile but display hyperphenylalaninemia and a predisposition to cataract formation. Surprisingly, HNF1 function in DCoH null mice is only slightly impaired, and mice are mildly glucose-intolerant in contrast to HNF1alpha null mice, which are diabetic. DCoH function as it pertains to HNF1 activity appears to be partially complemented by a newly identified homolog, DCoH2.
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PMID:Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene. 1201 Oct 81

The aims of this study were to estimate the prevalence of major maturity-onset diabetes of the young (MODY) subtypes in Spanish MODY families and to analyze genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the glucokinase (GCK), hepatic nuclear factor- HNF-1alpha and HNF4alpha genes using PCR-single strand conformation polymorphism and/or direct sequencing. In families carrying GCK mutations, the influence of genetic defects on fetal growth was investigated by comparing the birth weights of 32 offspring discordant for the mutations. Mutations in MODY genes were identified in 64% of the families. GCK/MODY2 mutations were the most frequently found, in 41%: seven novel (R369P, S411F, M298K, C252Y, Y108C, A188E, and S383L) and 2 already described mutations. Four pedigrees (18%) harbored mutations in the HNF-1alpha/MODY3 gene, including a previously unreported change (R271G). One family (4%) carried a novel mutation in the HNF-4alpha gene (IVS5-2delA), representing the first report of a MODY1 pedigree in the Spanish population. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3. Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin. The MODY1 patient was diagnosed at 15 yr of age. She developed intermittent microalbuminuria despite good metabolic control, and severe late-onset complications were common within her family. Mutations in the GCK/MODY2 gene are the most common cause of MODY in our population as recruited from pediatric and adolescent index patients. The inheritance of GCK defects by the fetus results in a reduction of birth weight. Clinical expression of MODY3 and MODY1 mutations, the second and third groups of defects found, was more severe, including the frequent development of chronic complications.
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PMID:Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. 1205 Feb 10


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