Construction of a fine genetic map in the rat model of type 1 diabetes for positional cloning

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The Long-Evans Tokushima Lean (LETL) rat, characterized by rapid onset of insulin-dependent (type 1) diabetes mellitus (IDDM), no sex difference in the incidence of IDDM,autoimmune destruction of pancreatic beta-cells, and no significant T-cell lymphopenia, is a desirable animal model for human IDDM.The first genetic analysis showed that an MHC-linked gene is involved in the pathogenesis of insulitis. So far, other genetic factors have not been revealed due to a low incidence (about 20%) of IDDM in this strain. We have established a diabetes-prone substrain of the LETL rat, named Komeda Diabetes-Prone (KDP) rat, showing a 100% development of insulitis and over 70% incidence of IDDM within 220 days. In this study, we performed the first genom-wide scan for non-MHC IDDM susceptibility genes in the KDP rat and identified a major IDDM susceptibility gene, termed Iddm/kdp1, in the region between Mox2 and D11M16Mit46 on rat chromosome (Chr) 11. Homozygosity for the KDP allele at this locus is shown to be essential for the development of moderate to severe insulitis and the onset of IDDM.Comparative mapping suggests that homologues of Iddm/kdp1 are located on human Chr 3 and mouse Chr 16 and would therefore be different from previous reported IDDM susceptibility genes. (J.Clin.Invest.1997.100 : 2015-2021.)