title: Smad2: a candidate gene for the murine autoimmune diabetes locus Idd21.1.
abstract: BACKGROUND
  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.
authors: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors: Sarah M
authors: SM
authors: Hook
authors: Amanda J
authors: AJ
authors: Phipps-Green
authors: Fathimath
authors: F
authors: Faiz
authors: Les
authors: L
authors: McNoe
authors: Cushla
authors: C
authors: McKinney
authors: Jade E
authors: JE
authors: Hollis-Moffatt
authors: Tony R
authors: TR
authors: Merriman
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics* / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D051899:Smad2 Protein; D016212:Transforming Growth Factor beta