Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diabetes-prone BioBreeding (BB) and Komeda diabetes-prone (KDP) rats are both spontaneous animal models of human autoimmune, T-cell-associated type 1 diabetes. Both resemble the human disease, and consequently, susceptibility genes for diabetes found in these two strains can be considered as potential candidate genes in humans. Recently, a frameshift deletion in Ian4, a member of the immune-associated nucleotide (Ian)-related gene family, has been shown to map to BB rat Iddm1. In the KDP rat, a nonsense mutation in the T-cell regulatory gene, Cblb, has been described as a major susceptibility locus. Following a strategy of examining the human orthologues of susceptibility genes identified in animal models for association with type 1 diabetes, we identified single nucleotide polymorphisms (SNPs) from each gene by resequencing PCR product from at least 32 type 1 diabetic patients. Haplotype tag SNPs (htSNPs) were selected and genotyped in 754 affected sib-pair families from the U.K. and U.S. Evaluation of disease association by a multilocus transmission/disequilibrium test (TDT) gave a P value of 0.484 for IAN4L1 and 0.692 for CBLB, suggesting that neither gene influences susceptibility to common alleles of human type 1 diabetes in these populations.
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PMID:Haplotype tag single nucleotide polymorphism analysis of the human orthologues of the rat type 1 diabetes genes Ian4 (Lyp/Iddm1) and Cblb. 1474 5

BB rats develop type 1 diabetes and WOKW rats facets of the metabolic syndrome. Both strains are common the RT1 (u) haplotype of major histocompatibility complex (MHC) which is essential for type 1 diabetes development in BB rats ( IDDM1). However, BB rats need an additional gene (lymphopenia, IDDM2, GIMAP5) to develop type 1 diabetes. Because WOKW lacks IDDM2 and does not develop hyperglycemia a congenic WOKW rat strain was generated recombining the region of chromosome 4 with IDDM2 onto the genetic background of WOKW rats (WOKW.4BB). These newly established rats and their parental WOKW rats were genetically and phenotypically characterized. Congenic WOKW.4BB rats showed a lymphopenic phenotype. The sequences of the highly polymorphic exon 2 of RT1-BB class II gene in WOKW, BB/OK, WOKW.4BB and LEW.1W rats were comparable and clearly showed the RT1 (u) haplotype. In addition, there were significant differences in metabolic traits between WOKW.4BB and parental WOKW. Although congenic WOKW.4BB rats were homozygous for IDDM1 and IDDM2 of the BB/OK rat none of WOKW.4BB rats developed hyperglycemia. This observation may be attributed to the idea that either WOKW.4BB rats need a third IDDM gene of BB/OK rats to develop hyperglycemia or WOKW background gene/s protect/s them for hyperglycemia.
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PMID:Iddm1 and Iddm2 homozygous WOK.4BB rats develop lymphopenia, but no hyperglycemia like the BB/OK rats. 2137 49

A mutation in the rat GIMAP5 gene predisposes for autoimmunity, most famously in the BB rat model of autoimmune type 1 diabetes mellitus. This mutation is associated with severe peripheral T lymphopenia, as is mutation of the same gene in mice, but the mechanism by which GIMAP5 normally protects T cells from death is unknown. GIMAP5 is a putative small GTPase, a class of proteins which often fulfil their functions in the vicinity of cellular membranes. The objective of this study was to determine the normal intracellular location of GIMAP5 in lymphoid cells. Combining studies in rat, mouse and human systems, novel monoclonal antibodies (mAbs) were used to examine the localization of GIMAP5 and the closely-related protein, GIMAP1, in lymphoid cells by means of confocal microscopy and sub-cellular fractionation combined with immunoblotting. Additionally, human Jurkat T cells that inducibly express epitope-tagged GIMAP5 were established and used in electron microscopy (EM). Endogenous GIMAP5 was found to be located in a membraneous compartment/s which was also detected by established markers of lysosomes. GIMAP1, by contrast, was found to be located in the Golgi apparatus. EM studies of the inducible Jurkat T cells also found GIMAP5 in lysosomes and, in addition, in multivesicular bodies. This study establishes that the endogenous location of GIMAP5 is in lysosomes and related compartments and provides a clearer context for hypotheses about its mechanism of action.
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PMID:The autoimmunity-related GIMAP5 GTPase is a lysosome-associated protein. 2148 83

GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype-driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene-gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded.
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PMID:GIMAP GTPase family genes: potential modifiers in autoimmune diabetes, asthma, and allergy. 2596 88