International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


Hattori M
Joslin Diabetes Center

Co-Authors: 1) Fujisawa T, 1) Noso S, 1) Hattori K, 1, 2) Lund T, 3) Haskins K, 4) Flavell R A, 5) Wakeland E K
Institutions: 1) Joslin Diabetes Center, 2) University College London, 3) University of Colorado, 4) Yale University, 5) University of Texas Southwestern Medical Center

Type 1 diabetes is a polygenic autoimmune disease in man and the NOD mouse. The genes in the MHC region are the most important in determining susceptibility or resistance to type 1 diabetes. The region (33.9 Mbp) centromeric to the Lmp2 gene of the NOD mouse was replaced with the same R209 region by introducing an intra-MHC recombinational hotspot from the B10.A(R209) mouse. This replacement prevented the development of diabetes (form 71 to 3%)and insulitis (from 61 to 15%). Similarly the replacement of the NOD MHC A, E and D region with the same R209 region prevented the development of diabetes (from 71 to 0%) and insulitis (from 61 to 3%).

We have established six congenic lines (A-F) with a homozygous r209/r209 segment in the region within 7.4 Mbp centromeric to the Lmp-2-hotspot, and two congenic lines (G, H) with a homozygous r209/r209 segment within a region 23 Mbp from the centromere. Our observation suggests that in addition to the MHC class II A there are at least four more MHC-linked type 1 diabetogenic genes in the 33.9 Mbp region centromeric to the Lmp2 gene, Idd1a (current interval: 3.5 Mbp) in line A and B, Idd1b (2.9 Mbp) in line C, Idd1c (13.9 Mbp) and Idd1d (7.3 Mbp) in line G. The importance of the MHC and its linked regions in the disease susceptibility represents the effects of multiple genes. Identification of all the MHC-linked diabetogenic genes in the NOD mouse should accelerate the studies of homologous genes in humans.

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