| First Author | Prochazka M | Year | 1987 |
| Journal | Mouse News Lett | Volume | 78 |
| Pages | 57-58 | Mgi Jnum | J:14125 |
| Mgi Id | MGI:62301 | Citation | Prochazka M, et al. (1987) Identification of a third recessive diabetogenic locus in NOD mice. Mouse News Lett 78:57-58 |
| abstractText | Full text of MNL contribution. 2. Identification of a third recessive diabetogenic locus in NOD mice. Non-obese diabetic (NOD) mice are a model for insulin-dependent diabetes (IDD) with autoimmune etiology. We previously reported that diabetes susceptibility in NOD is under polygenic control of autosomal loci. Based on the analysis of BC1 generation derived from Fl hybrids between NOD/Lt and a related but diabetes-resistant non-obese normal (NON/Lt) strain backcrossed to NOD/Lt we identified and localized two diabetogenic loci in NOD. The first locus, designated Idd-1, is tightly linked to H-2K region on Chr 17. The second locus, Idd-2, was assigned to Chr 9 on the basis of its association with Alp-1 and Thy-1 markers (M.N.L. 1986; 75:32). To determine the position of Idd-2 more precisely we used as an additional marker the cytochrome P450 gene located between Alp-1 and Mod-1. Using a cDNA probe specific for the P450-3 gene, we found a restriction fragment length polymorphism (RFLP) between NOD and NON. Analysis of genomic DNA from the diabetic BC1 mice indicated a tentative position of Idd-2 on the proximal end of Chr 9 between the centromere and the Thy-l/Alp-1 cluster. Because the incidence of diabetes in BC1 mice was low (9.5%) and 27% of the mice homozygous for NOD alleles of Chr 9 and 17 markers(and therefore presumably also for susceptibility alleles Idd-1s and Idd-2s of NOD) remained diabetes free, we tested the hypothesis that a third recessive locus was segregating. Non-diabetic BC1 males homozygous for NOD Chr 9 and 17 markers (assumed to be fixed for s alleles at Idd-1 and Idd-2) were backcrossed to NOD females with the prediction that if these BC1 males were diabetes-resistant because of heterozygosity at a third locus (Idd-3s/Idd-3r), the diabetes incidence in the second backcross (BC2) generation would theoretically be close to 50%. In this cross a diabetes incidence of 46% (27 of 59 mice, 12 males and 15 females) was obtained. This strongly supports the conclusion that NOD mice differ from NON by susceptibility alleles at only one additional locus, provisionally Idd-3. No linkage of Idd-3 to informative biochemical genetic markers segregating in BC2 has yet been found. Insulitis (leukocytic infiltrates in islets associated with erosion of beta cell mass) is a prominent histopathological lesion in the pancreas of NOD mice. It has been proposed previously that insulitis in NOD is controlled by a single recessive locus in comparison to the insulitis-free NON mice (Makino et al., Exp. Anim. 1985; 34:425). We performed a histological survey of pancreases from 139 diabetes-free BC1 mice in our study. Pancreases of only 17% of these mice were free of leukocytic infiltrates. Peri-insular lymphocyte aggregations were common in the remaining mice, with insulitis apparent in some of the islets in 37 of these mice. The detection of insulitis was not limited to segregants homozygous for either or both Idd-1s or Idd-2s loci (inferred from homozygosity for NOD-type alleles at marker genes on Chr 9 (Alp-1b) and 17 (H-2Kd). Presumably, an interaction between all NOD susceptibility loci (including Idd-3) is necessary for insulitis to be sufficiently widespread throughout the pancreas and culminate in hyperglycemia. Simultaneously, a similar backcross analysis was performed between NOD/Lt and C57BL/KsJ, selected because of its sensitivity to diabetogenic drugs and diabetes-obesity genes. Only one female of 115 BCl mice (0.9%) developed diabetes indicating that NOD/Lt and C57BL/KsJ mice differ at a minimum of 6 diabetogenic loci. On the other hand, this also illustrates that the two closely related strains, NOD and NON, share numerous diabetogenic susceptibility loci. Our results indicate that the genetic basis of diabetes susceptibility in NOD/Lt strain is attributable to interactions of susceptibility alleles at multiple autosomal loci. The polygenic basis of insulin-dependent diabetes inheritance in mice indicates that analysis of a diabetes-prone genotype in humans should not be limited to analysis of HLA-linked genes only. Location of non-MHC -linked diabetogenic genes in NOD should be valuable in suggesting other human chromosomes that may carry homologous loci. In humans, the THY1 and ALP1 loci are located on the long arm of Chr 11. Therefore this chromosome could be suggested as a potential site for a human diabetogenic locus analogous to Idd-2. (M. Prochazka, Leiter, D.L. Coleman) |
