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.
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.
Wicker
Linda S
LS
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK. linda.wicker@cimr.cam.ac.uk
Chamberlain
Giselle
G
Hunter
Kara
K
Rainbow
Dan
D
Howlett
Sarah
S
Tiffen
Paul
P
Clark
Jan
J
Gonzalez-Munoz
Andrea
A
Cumiskey
Anne Marie
AM
Rosa
Raymond L
RL
Howson
Joanna M
JM
Smink
Luc J
LJ
Kingsnorth
Amanda
A
Lyons
Paul A
PA
Gregory
Simon
S
Rogers
Jane
J
Todd
John A
JA
Peterson
Laurence B
LB
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D060908:CTLA-4 Antigen; D027682:Cation Transport Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D000099173:Natural Resistance-associated Macrophage Protein 1
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D060908:CTLA-4 Antigen; D027682:Cation Transport Proteins; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D000099173:Natural Resistance-associated Macrophage Protein 1; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556692:ICOS protein, human; C556694:Icos protein, mouse