Mapping of the IDDM Locus <i>Idd3</i> to a 0.35-cM Interval Containing the <i>Interleukin-2</i> Gene

Denny, Paul; Lord, Christopher J.; Hill, Natasha J.; Goy, Juliet V.; Levy, Elaine R.; Podolin, Patricia L.; Peterson, Laurence B.; Wicker, Linda S.; Todd, John A.; Lyons, Paul

doi:10.2337/diab.46.4.695

Cited by 101 publications

(68 citation statements)

References 17 publications

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“…IL2 and Il21 are adjacent genes on chromosome 3 in mice, and the analogous locus exists on chromosome 4 in humans. Both IL-2 and IL-21 are known to impact on the disease process, but a genetic lesion that would implicate either gene in the Idd3 effect has not yet been identified (1,2). Genetic linkage studies support an association of the IL2/IL21 region on human chromosome 4q27 with T1D (3), and this finding has been supported by a recent study in both T1D and RA patients (4).…”

supporting

confidence: 70%

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Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

McGuire

Vogelzang

Hill

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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IL-2 and IL-21 are two cytokines with great potential to affect autoimmune infiltration of nonlymphoid tissue, and are contained within the strongest non-MHC-linked locus for type 1 diabetes (T1D) susceptibility on the nonobese diabetic (NOD) mouse (Idd3). IL-21 is necessary for the development of diabetes in the NOD mouse, but a number of important studies argue that decreased expression of IL-2 explains Idd3. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. During our analyses of the IL-2/IL-21 interval, we found that mice segregate into one of two distinct expression profiles. In the first group, which includes the C57BL/6 strain, both Il2 and Il21 were expressed at low levels. In the other group, which includes the NOD strain, Il2 and Il21 were both highly expressed. However, because NOD IL-2 mRNA was relatively unstable, IL-2 production was remarkably similar between strains. The increased production of IL-21 in NOD mice was found to result from two single nucleotide polymorphisms within the distal promoter region that conferred increased binding affinity for the transcription factor Sp1. Our findings indicate that a loss of locus parity after decreased IL-2 mRNA stability ensures that the high-expressing IL-21 allele persists in nature and provides a basis for autoimmunity. type 1 diabetes ͉ cytokines ͉ transcription factor ͉ allele ͉ promoter

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supporting

confidence: 70%

“…A decade ago, and before IL-21 was identified, IL-2 was recognized to be the putative susceptibility gene for Idd3 (1). However, it remained unclear whether IL-2 promoted or inhibited diabetes development.…”

mentioning

confidence: 99%

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

McGuire

Vogelzang

Hill

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Subsequently, congenic strains have been successfully used to delineate smaller genetic intervals with the aim of identifying positional candidate genes. [32][33][34] Typical congenic intervals contain at least 400-600 known or predicted genes and hence some strategy for prioritisation of candidate genes is essential. The approach that we present here, expression analysis of overlapping congenic strains, provides an excellent method for narrowing the focus even further and identifying differentially expressed positional candidate genes.…”

Section: Discussionmentioning

confidence: 99%

Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes

et al. 2006

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“…IL-2 and IL-2R knockout mice manifest severe immune system abnormalities characterized by a lymphoadenopathy, splenomegaly, uncontrolled activation and proliferation of lymphocytes, and T cell infiltration of the bone marrow (32), indicating that IL-2 is a nonredundant determinant of T cell tolerance and autoimmunity. The IL-2 gene is also localized within a type 1 diabetes interval, and a functional polymorphism was observed for the IL-2 molecule in NOD mice (33,34) cell proliferation and apoptosis (35)(36)(37)(38). Pim1 is a serine/threonine kinase, and the protein cooperates specifically with c-Myc in lymphogenesis.…”

Section: Discussionmentioning

confidence: 99%

A Mutant Stat5b with Weaker DNA Binding Affinity Defines a Key Defective Pathway in Nonobese Diabetic Mice

Davoodi-Semiromi

Laloraya

Kumar

et al. 2004

Journal of Biological Chemistry

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A number of cytokines that finely regulate immune response have been implicated in the pathogenesis or protection of type 1 diabetes and other autoimmune diseases. It is, therefore, of pivotal importance to examine a family of proteins that serve as signal transducers and activators of transcription (STATs), which regulate the transcription of a variety of cytokines. We report here a defective gene (Stat5b) located on chromosome 11 within a previously mapped T1D susceptibility interval (Idd4) in the nonobese diabetic (NOD) mice. Our sequencing analysis revealed a unique mutation C1462A that results in a leucine to methionine (L327M) in Stat5b of NOD mice. Leu 327 , the first residue in the DNA binding domain of STAT proteins, is conserved in all identified mammalian STAT proteins. Homology modeling predicted that the mutant Stat5b has a weaker DNA binding, which was confirmed by DNA-protein binding assays. The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2R␤ and Pim1). Consequently, IL-2R␤ and Pim1 proteins were shown by Western blotting to have lower levels in NOD compared with normal B6 mice. These proteins have been implicated in immune regulation, apoptosis, activation-induced cell death, and control of autoimmunity. Therefore, the Stat5b pathway is a key molecular defect in NOD mice.Studies on the NOD mouse model that spontaneously develops T1D have shown that both B and T cells are necessary for

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Mapping of the IDDM Locus Idd3 to a 0.35-cM Interval Containing the Interleukin-2 Gene

Cited by 101 publications

References 17 publications

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes

A Mutant Stat5b with Weaker DNA Binding Affinity Defines a Key Defective Pathway in Nonobese Diabetic Mice

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