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Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.

Publication ,  Journal Article
Wicker, LS; Chamberlain, G; Hunter, K; Rainbow, D; Howlett, S; Tiffen, P; Clark, J; Gonzalez-Munoz, A; Cumiskey, AM; Rosa, RL; Howson, JM ...
Published in: J Immunol
July 1, 2004

At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.2. In this study, using a series of novel NOD.B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28. Genomic sequence comparison of the two functional candidate genes, Ctla4 and Icos, from the B6 (resistant at Idd5.1) and the NOD (susceptible at Idd5.1) strains revealed 62 single nucleotide polymorphisms (SNPs), only two of which were in coding regions. One of these coding SNPs, base 77 of Ctla4 exon 2, is a synonymous SNP and has been correlated previously with type 1 diabetes susceptibility and differential expression of a CTLA-4 isoform. Additional expression studies in this work support the hypothesis that this SNP in exon 2 is the genetic variation causing the biological effects of Idd5.1. Analysis of additional congenic strains has also localized Idd5.2 to a small region (1.52 Mb) of chromosome 1, but in contrast to the Idd5.1 interval, Idd5.2 contains at least 45 genes. Notably, the Idd5.2 region still includes the functionally polymorphic Nramp1 gene. Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs.

Duke Scholars

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

July 1, 2004

Volume

173

Issue

1

Start / End Page

164 / 173

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Molecular Sequence Data
  • Mice, Inbred NOD
  • Mice
  • Inducible T-Cell Co-Stimulator Protein
  • Immunology
  • Humans
  • Gene Expression Regulation
  • Diabetes Mellitus, Type 1
  • Chromosomes, Human, Pair 2
 

Citation

APA
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MLA
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Wicker, L. S., Chamberlain, G., Hunter, K., Rainbow, D., Howlett, S., Tiffen, P., … Peterson, L. B. (2004). Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol, 173(1), 164–173. https://doi.org/10.4049/jimmunol.173.1.164
Wicker, Linda S., Giselle Chamberlain, Kara Hunter, Dan Rainbow, Sarah Howlett, Paul Tiffen, Jan Clark, et al. “Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.J Immunol 173, no. 1 (July 1, 2004): 164–73. https://doi.org/10.4049/jimmunol.173.1.164.
Wicker LS, Chamberlain G, Hunter K, Rainbow D, Howlett S, Tiffen P, et al. Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol. 2004 Jul 1;173(1):164–73.
Wicker, Linda S., et al. “Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.J Immunol, vol. 173, no. 1, July 2004, pp. 164–73. Pubmed, doi:10.4049/jimmunol.173.1.164.
Wicker LS, Chamberlain G, Hunter K, Rainbow D, Howlett S, Tiffen P, Clark J, Gonzalez-Munoz A, Cumiskey AM, Rosa RL, Howson JM, Smink LJ, Kingsnorth A, Lyons PA, Gregory S, Rogers J, Todd JA, Peterson LB. Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol. 2004 Jul 1;173(1):164–173.

Published In

J Immunol

DOI

ISSN

0022-1767

Publication Date

July 1, 2004

Volume

173

Issue

1

Start / End Page

164 / 173

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Molecular Sequence Data
  • Mice, Inbred NOD
  • Mice
  • Inducible T-Cell Co-Stimulator Protein
  • Immunology
  • Humans
  • Gene Expression Regulation
  • Diabetes Mellitus, Type 1
  • Chromosomes, Human, Pair 2