| First Author | Prochazka M | Year | 1989 |
| Journal | Mouse News Lett | Volume | 84 |
| Pages | 91 | Mgi Jnum | J:14254 |
| Mgi Id | MGI:62426 | Citation | Prochazka M, et al. (1989) Mapping of Ldlr, Ets-1, T3d and T3e genes to the proximal region of Chromosome 9 in a linkage analysis of Idd-2 locus in NOD/Lt mice. Mouse News Lett 84:91 |
| abstractText | Full text of MNL contribution: f. Mapping of Ldlr, Ets-1, T3d and T3e genes to the proximal region of Chromosome 9 in a linkage analysis of Idd-2 locus in NOD/Lt mice. We have previously reported identification and localization of two loci involved in the polygenic control of development of spontaneous insulin-dependent diabetes (Idd) in Non-Obese Diabetic (NOD) mice. One locus (Idd-1) was found in tight association with H-2 on Chr 17, and a second locus (Idd-2) was assigned to the proximal part of Chr 9 in linkage with Thy-1. In our original study based on analysis of BC1 mice produced from an outcross between NOD/Lt and the closely related diabetes-resistant Non-Obese Normal (NON/Lt) inbred strain backcrossed to NOD/Lt, 19/200 BC1 mice developed diabetes and 16/19 were homozygous for NOD alleles Thy-1b and Apoa-1b (both genes tightly linked on the proximal part of Chr 9). Because the number of heterozygotes increased for the more distal markers P450-3 and Mod-1, we tentatively assigned Idd-2 between the centromere and Thy-1. However, studies of the contribution of Idd-2 to the diabetic phenotype were hindered by the lack of polymorphic markers for the 20 cM segment of Chr 9 between the centromere and Thy-1 such that the genotype of alleles at Idd-2 could be only inferred from the relatively loosely linked Thy-1 marker. In our effort to identify a marker with a closer association with diabetes than Thy-1 and Apoa-1, we explored a number of genes [the proto-oncogene Ets-1, low-density lipoprotein receptor (Ldlr), and T3d and T3e genes (homologues of CD3D and CD3E genes in human)] assigned to Chr 9 on the basis of somatic cell hybrid analysis but not mapped in relation to other well positioned markers on this chromosome for their potential localization in the region of interest. RFLP analysis of the congenic strain B6.PL-Thy-la using probes for Ets-1, Ldlr, T3d, and T3e revealed that this strain was carrying the donor (PL) allele for all of these genes indicating their relatively close linkage with Thy-1. Subsequently, we detected an RFLP between NOD/Lt and NON/Lt for Ets-1 and Ldlr (but not for T3d and T3e) and their preliminary analysis combined with typing of Thy-1, Apoa-1, P450-3, and Mod-1 in 65 BC1 offspring indicated the position of Ldlr is approximately 12 cM proximal, and Ets-1 is approximately 6 cM proximal from Thy-1/Apoa-1. Therefore, both Ets-1 and Ldlr map between the centromere and Thy-1 and should have a stronger association with the disease in our original 19 diabetic BC1 mice. Contrary to expectations, this analysis showed an increased number of mice with the F l pattern for Ets-1 and Ldlr. Thus, the strongest association remained with Thy-1/Apoa-1. These findings may indicate that the NOD susceptibility allele, Idd-2s, is not completely recessive so that occasional heterozygotes could develop diabetes. Alternatively, it may also be possible that Idd-2 is not located on Chr 9 and the original association with Thy-1/Apoa-1 was spurious. Experiments are now in progress to establish unequivocally the map distances and positions of Ets-1 and Ldlr before a definitive conclusion about Idd-2 is finally made. (M. Prochazka and E.H. Leiter) |
