Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci.

Abstract

Twenty diabetes susceptibility loci on 12 mouse chromosomes have been identified to control the development of type 1 diabetes at the level of either initiation of insulitis or progression from insulitis to overt diabetes or both. Previously, we demonstrated that the genetic control of T-cell proliferative unresponsiveness in nonobese diabetic (NOD) mice is linked to Idd4 on mouse chromosome 11. Here, we show by congenic mapping of three newly generated NOD.B6Idd4 diabetes-resistant mouse strains that Idd4 is limited to a 5.2-cM interval of chromosome 11. This B6-derived region expressed in NOD.B6Idd4A mice maps between the D11Nds1 (43.8 cM) and D11Mit38/D11Mit325 (49.0 cM) markers and dramatically reduces the development of both insulitis and type 1 diabetes. NOD.B6Idd4B and NOD.B6Idd4C mice, which carry a smaller B6-derived segment of chromosome 11 that spans <5.2 cM distal to D11Nds1, exhibit protection against type 1 diabetes with the restoration of T-cell proliferation. Our findings suggest that diabetes resistance conferred by Idd4 may be mediated by the Idd4.1 and Idd4.2 subloci. Idd4.1 is localized in the D11Nds1 interval that influences both diabetes and insulitis. Idd4.2 is localized within the D11Mit38/325 interval that mainly influences diabetes incidence and restores T-cell proliferative responsiveness. Three potential candidate genes, platelet activating factor acetylhydrolase Ib1, nitric oxide synthase-2, and CC chemokine genes, are localized in the 5.2-cM interval.