Search

The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes mellitus (T1DM) with an autosomal recessive mode of inheritance. T1DM susceptibility loci could be localized on chromosome (RNO) 20 in the major histocompatibility complex region (Iddm1) and on RNO1 (Iddm8, Iddm9) in a BN backcross cohort. In this study the impact of the different susceptibility regions on diabetes development was investigated in a backcross population of the diabetes-resistant PAR strain. A cohort of 130 [(PAR x LEW.1AR1-iddm) x LEW.1AR1-iddm] N2 rats was monitored for blood glucose and analyzed by linkage analysis. Sixteen percent of the PAR backcross animals developed T1DM. Genetic analysis revealed significant linkage to T1DM in the MHC region on RNO20p12. In contrast to the linkage analysis of the BN backcross cohort, only one susceptibility locus for T1DM could be identified on RNO1. This susceptibility region on RNO1 mapped to the telomeric end corresponding to Iddm8. Eighty-nine percent of diabetic PAR backcross animals were homozygous for Iddm8. The Iddm9 diabetes susceptibility region showed no linkage to diabetes in the PAR backcross cohort. The data of this study provide evidence that the mutation leading to T1DM in the LEW.1AR1-iddm rat is located at the telomeric end of RNO1 corresponding to Iddm8.

The LEW.1AR1-iddm/Ztm rat is a new animal model of type 1 diabetes mellitus, which shows an autosomal recessive mode of inheritance for the diabetes-inducing gene. The aim of this study was to define predisposing loci of the diabetic syndrome by linkage analysis using microsatellite markers. A backcross population of 218 rats (BN x LEW.1AR1-iddm) x LEW.1AR1-iddm was analyzed using 157 polymorphic microsatellite markers covering the entire genome. Three genomic regions showed a significant linkage to the diabetic syndrome. The first susceptibility locus on rat Chromosome (RNO) 1 (LOD score 4.13) mapped to the region 1q51-55, which codes for potential candidate genes like Ins1 and Nkx2-3. The second susceptibility locus was also localized on RNO1 in the centromeric region 1p11 (LOD score 2.7) encompassing the Sod2 gene. The third quantitative trait loci (LOD score 2.97) was located on RNO20 within the major histocompatibility complex region. Comparative mapping revealed that the homologous regions in the human genome contain the IDDM loci 1, 5, 8, and 17. The identification of diabetes susceptibility regions of the genetically uniform LEW.1AR1-iddm rat strain will pave the way toward a detailed characterization of the loci conferring diabetes development as well as their functional relevance for the pathogenesis of type 1 diabetes mellitus.