Secondary literature sources for ICA69
The following references were automatically generated.
- Bonner SM et al.
- Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression.
- J Biol Chem. 2012; 287: 17882-93
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ICA69 (islet cell autoantigen 69 kDa) is a protein implicated in type 1 diabetes mellitus in both the non-obese diabetic (NOD) mouse model and humans. ICA69 is encoded by the Ica1 gene on mouse chromosome 6 A1-A2. We previously reported reduced ICA69 expression in the thymus of NOD mice compared with thymus of several non-diabetic mouse strains. We propose that reduced thymic ICA69 expression could result from variations in transcriptional regulation of the gene and that polymorphisms within the Ica1 core promoter may partially determine this transcriptional variability. We characterized the functional promoter of Ica1 in NOD mice and compared it with the corresponding portions of Ica1 in non-diabetic C57BL/6 mice. Luciferase reporter constructs demonstrated that the NOD Ica1 promoter region exhibited markedly reduced luciferase expression in transiently transfected medullary thymus epithelial (mTEC(+)) and B-cell (M12)-derived cell lines. However, in a non-diabetic strain, C57BL/6, the Ica1 promoter region was transcriptionally active when transiently transfected into the same cell lines. We concomitantly identified five single nucleotide polymorphisms within the NOD Ica1 promoter. One of these single nucleotide polymorphisms increases the binding affinity for the transcription factor AIRE (autoimmune regulator), which is highly expressed in thymic epithelial cells, where it is known to play a key role regulating self-antigen expression. We conclude that polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells, thus providing a novel mechanistic explanation for the loss of immunologic tolerance to this self-antigen in autoimmunity.
- Hiller M et al.
- Conserved introns reveal novel transcripts in Drosophila melanogaster.
- Genome Res. 2009; 19: 1289-300
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Noncoding RNAs that are-like mRNAs-spliced, capped, and polyadenylated have important functions in cellular processes. The inventory of these mRNA-like noncoding RNAs (mlncRNAs), however, is incomplete even in well-studied organisms, and so far, no computational methods exist to predict such RNAs from genomic sequences only. The subclass of these transcripts that is evolutionarily conserved usually has conserved intron positions. We demonstrate here that a genome-wide comparative genomics approach searching for short conserved introns is capable of identifying conserved transcripts with a high specificity. Our approach requires neither an open reading frame nor substantial sequence or secondary structure conservation in the surrounding exons. Thus it identifies spliced transcripts in an unbiased way. After applying our approach to insect genomes, we predict 369 introns outside annotated coding transcripts, of which 131 are confirmed by expressed sequence tags (ESTs) and/or noncoding FlyBase transcripts. Of the remaining 238 novel introns, about half are associated with protein-coding genes-either extending coding or untranslated regions or likely belonging to unannotated coding genes. The remaining 129 introns belong to novel mlncRNAs that are largely unstructured. Using RT-PCR, we verified seven of 12 tested introns in novel mlncRNAs and 11 of 17 introns in novel coding genes. The expression level of all verified mlncRNA transcripts is low but varies during development, which suggests regulation. As conserved introns indicate both purifying selection on the exon-intron structure and conserved expression of the transcript in related species, the novel mlncRNAs are good candidates for functional transcripts.
- Dogra RS, Vaidyanathan P, Prabakar KR, Marshall KE, Hutton JC, Pugliese A
- Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas.
- Diabetologia. 2006; 49: 953-7
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AIMS/HYPOTHESIS: Autoimmunity to insulin, glutamic acid decarboxylase and the tyrosine-phosphatase-like protein IA-2 is associated with type 1 diabetes. The production of self-molecules in thymus and secondary lymphoid tissues is critical for self-tolerance; reduced levels may impair tolerance and predispose to autoimmunity, as shown for insulin. Alternative splicing causes differential expression of IA-2 gene (PTPRN) transcripts and IA-2 protein in human thymus and spleen compared with pancreas. IA-2 sequences not present in lymphoid tissues become autoimmune targets in type 1 diabetes. The beta cell molecule islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an autoantigen in the non-obese diabetic (NOD) mouse, a model of type 1 diabetes. IGRP is a candidate autoantigen in the human disease, but robust assays for IGRP autoantibodies and/or autoreactive T cells are not available. Both full-length and IGRP splice variants encoded by the G6PC2 gene are expressed in the pancreas. In this study we tested the hypothesis that IGRP splice variants could be differentially expressed in thymus and spleen compared with the pancreas. METHODS: We evaluated the expression of G6PC2 transcripts in matched human thymus, spleen and pancreas specimens by RT-PCR. RESULTS: Alternative splicing results in differential expression of G6PC2 transcripts in thymus and spleen compared with pancreas. The full-length transcript is expressed in human pancreas but not in thymus or spleen. Five alternative spliced forms are always expressed in pancreas but those lacking exons 2, 3 and 4, alone or in combination, were rarely detected in thymus or spleen. CONCLUSIONS/INTERPRETATION: Differential tissue expression might favour autoimmune responses to IGRP in humans; target epitopes may be encoded by exons 3 and 4, or at the junctions of the conserved exons in the spliced transcripts. This information may aid in designing synthetic peptides for the identification of IGRP-specific autoreactive T cells in patients with type 1 diabetes.
- Levisetti MG, Suri A, Vidavsky I, Gross ML, Kanagawa O, Unanue ER
- Autoantibodies and CD4 T cells target a beta cell retroviral envelope protein in non-obese diabetic mice.
- Int Immunol. 2003; 15: 1473-83
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We determined that, over a biologic time interval, from 4 to 8 weeks of age, female non-obese diabetic (NOD) mice develop antibodies against pancreatic beta-cell-surface antigens depending upon the presence of both the MHC class II susceptibility allele, I-A(g7), and other NOD background genes. We generated a mAb from a pre-diabetic NOD mouse that binds to the surface of insulinoma cells and isolated mouse beta cells, and identified the target as a retroviral envelope glycoprotein expressed on pancreatic beta cells. The cloned and expressed sequence for this protein was recognized by the mAb. The antibody as well as sera from pre-diabetic NOD mice recognized the recombinant protein. Spontaneous T cell reactivity against a peptide from the cloned protein was found in NOD mice. In conclusion, a beta cell retroviral envelope protein is a target antigen that is selected by the NOD mouse immune system early in the pathogenesis of autoimmune diabetes.
- Vazza G, Picelli S, Bozzato A, Mostacciuolo ML
- Identification and characterization of C3orf6, a new conserved human gene mapping to chromosome 3q28.
- Gene. 2003; 314: 113-20
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This study reports the characterization of a novel human gene, chromosome 3 open reading frame 6 (C3orf6), mapped to chromosome 3q28, within the critical region of hereditary spastic paraplegia SPG14 locus. Based on computational "spliced" EST alignment and RT-PCR, two C3orf6 transcript variants were identified. The longer C3orf6 transcript contains a 1449-nt ORF, encoding a protein of 482 aa, while the shorter variant contains a 921-nt ORF, encoding for a protein of 306 aa. C3orf6 gene is organised on 12 exons and the shorter transcript comes from an alternative splicing event skipping exon 6. The two mRNA are differentially expressed in brain and in several other human tissues with a predominant level for the shorter transcript. By database analysis, EST assembling and RT-PCR, we identified the transcripts of mouse and rat C3orf6 orthologous genes. The involvement of C3orf6 in the spastic paraplegia was investigated by sequencing all coding exons and flanking sequences in the SPG14 family, excluding the presence of causative mutations.
- Tran P et al.
- Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms.
- Mamm Genome. 2002; 13: 483-92
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Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine. Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to alter risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications, and certain cancers. Little is known about MTHFR regulation, since the complete cDNA and gene sequences have not been determined. In earlier work, we isolated and expressed a 2.2-kb human cDNA comprised of 11 coding exons, and we demonstrated that it encoded an active 70-kDa isoform. However, transcript sizes of approximately 7.5 kb and 9.5 kb and the presence of a second isoform of 77 kDa on Western blots suggested that cDNA sequences were incomplete. In this report, we characterized the complete cDNA and gene structure in human and mouse. Variable 5? and 3? UTR regions were identified, resulting in transcript heterogeneity. The 5? and 3? termini of the MTHFR cDNA were found to overlap with the 5? terminus of a chloride ion channel gene (CLCN-6) and the 3? terminus of an unidentified gene, respectively; this finding has resulted in finer mapping of MTHFR on Chromosome (Chr) 1p36.3. Ribonuclease protection assays identified clusters of transcriptional start sites, suggesting the existence of multiple promoters. MTHFR has several polyadenylation sites creating 3?UTR lengths of 0.2 kb-5.0 kb or 0.6 kb-4.0 kb in human and mouse, respectively. In both species, the previously reported exon 1 was redefined to approximately 3.0 kb in length and shown to be alternatively spliced. An important splice variant contains novel coding sequences; this cDNA was expressed and shown to encode the isozyme of 77 kDa. Our results, which suggest intricate regulation of MTHFR, will facilitate additional regulatory and functional studies of the different isoforms.
- Diez J et al.
- Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen.
- Diabetes. 2001; 50: 895-900
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Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells in genetically susceptible individuals. Growing evidence suggests that genetically determined variation in the expression of self-antigens in thymus may affect the shaping of the T-cell repertoire and susceptibility to autoimmunity. For example, both allelic variation and parent-of-origin effects influence the thymic expression of insulin (a known type 1 diabetes autoantigen), and insulin gene transcription levels in thymus inversely correlate with susceptibility in both humans and transgenic models. It is unclear why patients lose tolerance to IA-2 (insulinoma-associated tyrosine phosphatase-like protein, or islet cell antigen 512 [ICA512]), especially because IA-2 polymorphisms are not associated with type 1 diabetes. We report that alternative splicing determines differential IA-2 expression in islets compared with thymus and spleen. Islets express full-length mRNA and two alternatively spliced transcripts, whereas thymus and spleen exclusively express an alternatively spliced transcript lacking exon 13. This encodes for the transmembrane (TM) and juxta-membrane (JM) domains that comprise several type 1 diabetes target epitopes, supporting the concept that tolerance to IA-2 epitopes not expressed in lymphoid organs may not be achieved. We propose differential splicing as a regulatory mechanism of gene expression playing a permissive role in the development of autoimmune responses to IA-2. Our findings also show that candidate gene expression studies can help in dissecting the complex genetic determinants of a multifactorial disease such as type 1 diabetes.
- Conway EM et al.
- Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions.
- Blood. 2000; 95: 1435-42
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Survivin is a member of the inhibitor of apoptosis protein (IAP) family that is believed to play a role in oncogenesis. To elucidate further its physiologic role(s), we have characterized the murine survivin gene and complementary DNA (cDNA). The structural organization of the survivin gene, located on chromosome 11E2, is similar to that of its human counterpart, both containing 4 exons. Surprisingly, 3 full-length murine survivin cDNA clones were isolated, predicting the existence of 3 distinct survivin proteins. The longest open reading frame, derived from all 4 exons, predicts a 140-amino acid residue protein, survivin(140), similar to human survivin, which contains a single IAP repeat and a COOH-terminal coiled-coil domain that links its function to the cell cycle. A second cDNA, which retains intron 3, predicts the existence of a 121-amino acid protein, survivin(121) that lacks the coiled-coil domain. Removal of exon 2-derived sequences by alternative pre-messenger RNA (mRNA) splicing results in a third 40-amino acid residue protein, survivin(40), lacking the IAP repeat and coiled-coil structure. Predictably, only recombinant survivin(140) and survivin(121) inhibited caspase-3 activity. All 3 mRNA species were variably expressed during development from 7.5 days postcoitum. Of the adult tissues surveyed, thymus and testis accumulated high levels of survivin(140) mRNA, whereas survivin(121)-specific transcripts were detected in all tissues, while those representing survivin(40) were absent. Human counterparts to the 3 survivin mRNA transcripts were identified in a study of human cells and tissues. The presence of distinct isoforms of survivin that are expressed differentially suggests that survivin plays a complex role in regulating apoptosis. (Blood. 2000;95:1435-1442)
- Anand S, Batista FD, Tkach T, Efremov DG, Burrone OR
- Multiple transcripts of the murine immunoglobulin epsilon membrane locus are generated by alternative splicing and differential usage of two polyadenylation sites.
- Mol Immunol. 1997; 34: 175-83
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The human C epsilon gene produces a number of alternatively spliced heavy chain transcripts of which some encode functional IgE isoforms. We now show that differentially processed epsilon mRNA variants also exist in the mouse and are generated by differential polyadenylation and alternative splicing of primary epsilon chain transcripts. The two poly(A) sites of the mouse membrane transcripts were identified in the present study by RACE-PCR analysis. The first poly(A) site is located 743 nt downstream from the beginning of the second membrane exon (M2) and contains the same non-consensus AGTAAA signal sequence as the single poly(A) site of the human membrane transcripts. The second poly(A) site is located almost 500nt further downstream and is characterized by an AAGAAA hexamer. This poly(A) site contains a (G+T) rich element downstream to the site of cleavage and polyadenylation and is preferentially utilized by the membrane epsilon transcripts. Additional diversity of epsilon transcripts is generated by alternative splicing between the last constant region exon (CH4) and the two membrane exons (M1 and M2). The alternatively spliced transcripts include two variants that skip the first membrane exon and encode epsilon heavy chains that lack the transmembrane domain. The third variant is generated by splicing to an internal site in M2 and codes for a membrane isoform that is 10 amino acids shorter in the cytoplasmic domain than the classical membrane IgE. Although little amino-acid sequence homology exists between the murine epsilon chain isoforms and their human counterparts, the pattern of splicing is rather conserved between the two species.
- Illges H, Braun M, Peter HH, Melchers I
- Analysis of the human CD21 transcription unit reveals differential splicing of exon 11 in mature transcripts and excludes alternative splicing as the mechanism causing solubilization of CD21.
- Mol Immunol. 1997; 34: 683-93
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CD21 is found in a soluble form at low levels in normal human sera and at elevated levels in sera from patients with EBV-associated diseases and B-CLL. Ablation of complement, injection of recombinant soluble CD21 and knock-out of CD21 in mice by gene targeting interfere with T-cell-dependent immune responses, suggesting that in vivo-generated soluble CD21 may exert immunoregulatory functions. Soluble CD21 has a molecular weight of 130,000/135,000, which is equivalent to the entire extracellular domain. Soluble forms of membrane-anchored molecules may be generated by proteolytic cleavage of the extracellular portion or by the exclusion of the hydrophobic transmembrane region via alternative splicing. To delineate whether alternative splicing of CD21 mRNA creates transcripts encoding for the soluble form of CD21 we analyzed by PCR CD21 expression in PBLs, spleen, tonsils, bone marrow and in various cell lines. We found that all CD21 mRNA species contained the transmembrane exons, thus excluding alternative splicing as a factor contributing to the serum pool of soluble CD21. Differential splicing of the CD21 transcription unit has also been suggested for exon 11. Within the CD21 gene exons 3, 7 and 11 have a high degree of homology. However, we found in malignant human cell lines and primary lymphocytes from blood, bone marrow, tonsils and spleen that exon 11, but not exon 3 or 7, is subject to alternative splicing. We cloned and sequenced the intron preceding exon 11 and found that the surrounding splice sites match consensus splice sites. In conclusion, we show that human CD21 exon 11 is alternatively spliced in malignant cell lines of lymphoid origin and in purified lymphocytes from blood, tonsils, bone marrow and spleen. We found that both exon 11 lacking and exon 11 containing transcripts are always coexpressed and the ratio of the two forms is > 1. Moreover, we exclude the possibility that alternative splicing of the transmembrane region is the mechanism leading to soluble CD21.
- Arden SD et al.
- Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient.
- J Clin Invest. 1996; 97: 551-61
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Cell-mediated autoimmune attack directed against islet proteins of approximately 38 kD in size has been associated with type 1 diabetes. A novel murine cDNA encoding an antigen of this size was cloned using a screening procedure based on the proliferative response of a human diabetic T cell clone (1C6) to a recombinant antigen epitope library. Membrane preparations from COS 7 cells transfected with the full-length 1,267-bp cDNA elicited a proliferative response from the reporter T cells comparable to that of the defined peptide epitope and native insulinoma antigen. In vitro translation and transfection experiments suggested that the protein is initially synthesized as a 44-kD protein and then processed to the native 38-kD form through the proteolytic removal of a 54-aa NH2-terminal mitochondrial targeting sequence. Differential centrifugation, Percoll density gradient centrifugation, and immunofluorescence studies confirmed localization of the antigen to mitochondria. Northern blot, Western blot, and 1C6 T cell proliferation assays showed that, although imogen 38 was more highly expressed in beta cell than alpha cell lines, it was also present in other tissues. It is concluded that imogen 38 may be a target for bystander autoimmune attack in diabetes rather than a primary autoantigen.
- Carson DA
- The value of epitope mapping in autoimmune diseases.
- J Clin Invest. 1994; 94: 1713-1713