Smad2: A candidate gene for the murine autoimmune diabetes locus Idd21.1

Academic Article


  • Context: Congenic NOD.ABH D18Mit8-D18Mit214 mice, which contain greater than 12.8 Mb of DNA encompassing Idd21.1 from diabetes-resistant Biozzi/ABH mice, have a lower frequency of diabetes compared with the parental nonobese diabetic (NOD) strain, possibly due to reduced pathogenicity of β-islet-infiltrating immune cells. Objective: The objective of the study was to identify an Idd21.1 candidate gene. Methods: The methods used in the study were adoptive transfer into scid mice lacking an adaptive immune system; dendritic cell phenotyping and gene expression analysis; and fine-mapping Idd21.1 by congenic mapping. Results: Diabetes incidences of NOD.scid.ABH D18Mit8-D18Mit214 mice receiving splenocytes from NOD and NOD.ABH D18Mit8-D18Mit214 were similar to that previously observed in NOD.scid recipients, suggesting that the diabetes resistance in NOD.ABH D18Mit8-D18Mit214 is primarily mediated by the adaptive immune system, findings supported by adoptive transfer of CD4 + T cells. In activated dendritic cells, there were no conclusive differences in cytokine profiles and activation marker expression. However, microarray analysis comparing gene expression between activated dendritic cells from NOD and NOD.ABH D18Mit8-D18Mit214 revealed that Smad2, in a maximal 6.5-Mb region to which Idd21.1 was further resolved by congenic mapping, was differentially expressed (increased in NOD). Quantitative real-time PCR confirmed the differential expression of Smad2, and other genes in the TGF-β signaling pathway, in activated dendritic cells. Conclusions: These results implicate Smad2 as an Idd21.1 candidate and Smad2 and the TGF-β signaling pathway in activated dendritic cells in diabetogenesis. With suggestive evidence from human genome-wide association studies supporting a role for SMAD7 in human type 1 diabetes, a comprehensive genetic investigation of the SMAD genes in type 1 diabetes is warranted. Copyright © 2011 by The Endocrine Society.
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    Digital Object Identifier (doi)

    Author List

  • Hook SM; Phipps-Green AJ; Faiz F; McNoe L; McKinney C; Hollis-Moffatt JE; Merriman TR
  • Volume

  • 96
  • Issue

  • 12