Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amino acid 57 of DQ beta chains is of functional importance as it influences peptide binding, is part of B and T cell epitopes, and is associated with susceptibility and resistance to insulin-dependent diabetes mellitus and humoral immunodeficiencies. Polymorphism of codon 57 is conserved in primates and in HLA class II B genes implying that balancing selection operates on this residue. Previously, three DQB1 allele pairs have been described, that only differ at residue 57. In an African-American Black individual with the HLA phenotype A23.30;B58,63;Cw6;DR18,12;DR52;DQ5,2, we found a fourth example of this dimorphism: the new DQB1*0203 allele, that was identical to DQB1*0202 except for codon 57, which encodes aspartic acid and alanine respectively in the two alleles. The class II haplotype carrying the new allele was deduced to be DRB1*0302,DRB3*0101,DQA1*05011,DQB1*0203.
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PMID:DQB1*0202 and the new DQB1*0203 allele: a fourth pair of DQB1 alleles differing only at codon 57. 909 36

This article focuses on recent developments that have defined the autoimmune nature of this entity and its genetic basis, especially the crucial roles of aspartic acid at position 57 of the DQ beta chain and arginine at position 52 of the DQ alpha chain of the HLA complex on chromosome 6 in conferring susceptibility; other genetic markers on other genes are mentioned. These genetic markers help to explain the worldwide differences in prevalence and incidence of type 1 diabetes. Because the autoimmune process may be gradual, markers of beta pancreatic cell damage, such as islet cell antibodies, glutamic acid decarboxylase antibodies, and insulin autoantibodies, coupled with evidence of progressive failure of insulin secretion may be used to predict the future onset of disease. In turn, accurate prediction may permit preventive intervention. Two intervention trials are mentioned: (1) Diabetes Prevention Trial for Type 1, a multicenter trial in the United States using insulin; and (2) European Nicotinamide Diabetes Intervention Trial in Europe using nicotinamide as the preventive or delaying agent. These first steps reflect the remarkable progress and understanding of this major problem of childhood and the hopes for its future prevention.
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PMID:Aspects of the etiology, prediction, and prevention of insulin-dependent diabetes mellitus in childhood. 913 Sep 20

Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.
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PMID:[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America]. 950 14

The molecular mechanism by which some, but not all, variants of encephalomyocarditis (EMC) virus selectively infect pancreatic beta-cells in mice and induce IDDM has been an enigma for more than a decade. We report here that the binding site of the EMC viral capsid protein VP1 determines viral diabetogenicity. Recombinant chimeric EMC viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 of the major capsid protein VP1 bind poorly to beta-cells. In contrast, recombinant chimeric EMC viruses containing alanine or glycine at position 152 of the VP1 bind efficiently to and infect beta-cells, resulting in the development of diabetes. Three-dimensional molecular modeling reveals that the van der Waals interactions are greater and the residues surrounding position 152 of the VP1 are more closely packed in recombinant chimeric viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 than in recombinant chimeric viruses containing alanine or glycine at the same position. Our studies reveal that the surface areas surrounding alanine or glycine at position 152 of the VP1 are more accessible, thus increasing the availability of the binding sites for attachment to beta-cell receptors and resulting in viral infection and the development of diabetes.
Diabetes 1998 Apr
PMID:Determination of encephalomyocarditis viral diabetogenicity by a putative binding site of the viral capsid protein. 956 90

Susceptibility to the human autoimmune disease IDDM is strongly associated with those haplotypes of the major histocompatibility complex (MHC) carrying DQB1 alleles that do not encode aspartic acid at codon 57. Similarly, in a spontaneous animal model of this disease, the NOD mouse, the genes of the MHC play an important role in the development of diabetes. The DQB1 homolog in NOD mice, I-Ab(g7), encodes a histidine at codon 56 and a serine at codon 57, while all other known I-Ab alleles encode proline and aspartic acid, respectively, at these positions. We therefore mutated the NOD I-Ab allele to encode proline at position 56 and aspartic acid at position 57 and introduced this allele onto the NOD genetic background to study the effect of these substitutions on susceptibility to diabetes. No transgenic mice developed diabetes by 8 months of age, and transgenic mice had markedly reduced lymphocytic infiltration in the pancreas compared with nontransgenic littermates. Furthermore, splenocytes from transgenic mice failed to proliferate or secrete gamma-interferon in response to a panel of beta-cell autoantigens, although the mice did produce beta-cell specific antibodies. Interestingly, the proportion of IgG1 and IgE relative to IgG2a comprising these autoantibodies was much greater in transgenic mice compared with nontransgenic control mice. Finally, T-cells from transgenic mice inhibited the adoptive transfer of diabetes to irradiated recipients. This inhibition was partially reversed by treatment of the recipients with a combination of anti-interleukin (IL)-4 and anti-IL-10 monoclonal antibodies. Thus, a transgenic class II MHC allele encoding aspartic acid at B57 prevents diabetes, in part, by promoting the production of IL-4 and IL-10, which interfere with the effector phase of the diabetic process.
Diabetes 1998 Oct
PMID:Prevention of diabetes in NOD mice by a mutated I-Ab transgene. 975 94

We report on the role of HLA-DQA1 and DQB1 alleles in determining susceptibility to insulin-dependent diabetes mellitus (IDDM) in Hong Kong Chinese and investigate whether these alleles affect the age of onset of the disease. We studied 76 unrelated Chinese patients and 250 controls. There was no apparent predisposing effect of non-aspartic acid residues at position 57 of the DQ beta chain (Asp57-) but there was an excess of homozygous genotypes containing arginine at position 52 of the DQ alpha chain (Arg52+). This excess was mainly attributable to the genotype DQA1*0301/DQA1*05011 in early-onset disease. There was a significant excess of heterodimers of DQ alpha and DQ beta carrying Arg52+ and Asp57- in both early-onset and late-onset disease, but the excess in early-onset disease was mainly attributable to a single heterodimer formed by DQA1*05011 and DQB1*0201. Of three DQA1/DQB1 genotypes containing a double dose of Arg52+ and Asp57-, only one had a strong association with both early-onset and late-onset disease. We show that early-onset IDDM and late-onset IDDM in Chinese may be separated on the basis of their associated DQA1 and DQB1 genotypes and we conclude that previously reported associations of IDDM with Arg52+ and Asp57- residues in Chinese are secondary to specific combinations of DQA1 and DQB1 alleles. We also show that DRB1 molecules play a distinct role in determining susceptibility to early-onset IDDM but the greatest effect is exerted by specific DR/DQ genotypic combinations.
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PMID:Strong association between DQA1/DQB1 genotype and early-onset IDDM in Chinese: the association is with alleles rather than specific residues. 977 26

The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.
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PMID:Thymic positive selection and peripheral activation of islet antigen-specific T cells: separation of two diabetogenic steps by an I-A(g7) class II MHC beta-chain mutant. 979 72

Attachments of cultured dorsal root ganglion (DRG) neurons to the extracellular matrix (ECM) proteins (type I and IV collagens, laminin and fibronectin) and the adhesion ligand arginine-glycine-aspartic acid (RGD) were impaired in mice 2 weeks after the induction of diabetes by streptozotocin (STZ). However, administration of the aldose reductase inhibitor, ONO-2235, to the STZ-diabetic mice for 1 week restored DRG neuronal attachment to the ECM proteins and RGD to a level close to normal mice. These results suggest that activation of the aldose reductase and subsequent metabolic disorders in diabetic animals may play an important role in detrimental alterations of the neuronal cell-surface receptors for the ECM proteins.
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PMID:Administration of an aldose reductase inhibitor, ONO-2235, to streptozotocin-diabetic mice restores reductions of DRG neuronal attachment to extracellular matrix proteins in vitro. 1021 59

Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.
Diabetes 1999 Feb
PMID:A point mutation inactivating the sulfonylurea receptor causes the severe form of persistent hyperinsulinemic hypoglycemia of infancy in Finland. 1033 22

Thirty-four insulin-dependent diabetes mellitus (IDDM) patients from North India were studied with respect to their HLA class II alleles including those of the DRB1, DQA1, DQB1 and DPB1 loci, using the polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes (SSOP). They were compared with the class II alleles of 94 normal adult controls from the same ethnic background. The results show a statistically significant increase of DRB1*03011 (p < 0.00001), DQB1*0201 (p < 0.007), DQA1*0501 (0.0027) and DPB1*2601 (p < 0.0042) in patients compared to controls. DR*04 was not significantly increased. However, homozygosity for DRB1*03011 was increased more than expected. DRB1*1501 and *1502 did not show a significant decrease in the patients. However, DRB1*0701 was decreased significantly, but this difference did not remain significant when the p value was corrected for the number of alleles tested. Similarly, DPB1*2601 was increased significantly in the patients but did not remain significant after p was corrected for the number of alleles tested. However, DPB1*2601 was increased, and remained significant after correction, in patients not having HLA-DR3. We also studied the possible role of aspartic acid at codon 57 of the DQ beta chain in protection against development of diabetes, and arginine at codon 52 of the DQ alpha chain in susceptibility. We observed an increase in non-Asp57 alleles in DQ beta and Arg52 in DQ alpha in the patients, however, this effect seems to be due to the fact that the most prevalent haplotype in diabetic patients: DRB1*03011-DQA1*0501-DQB1*0201, has DQB1 and DQA1 alleles which carry non-Asp57 and Arg52, respectively.
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PMID:Associations of MHC class II alleles with insulin-dependent diabetes mellitus (IDDM) in patients from North India. 1040 2


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