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

Long-Evans德岛瘦（LETL）大鼠是一种理想的人胰岛素依赖型糖尿病（IDDM）动物模型，其特点是发病迅速，发病率无性别差异，胰岛β细胞自身免疫性破坏，T淋巴细胞无明显减少。到目前为止，其他遗传因素尚未被发现，由于低发病率（约20%）的胰岛素依赖型糖尿病在这个菌株。我们已经建立了一个糖尿病易感的LETL大鼠亚系，命名为Komeda糖尿病易感（KDP）大鼠，显示了100%的胰岛炎的发展和超过70%的发病率在220天内的IDDM。在这项研究中，我们进行了第一次全基因组扫描的非MHC IDDM易感基因在KDP大鼠，并确定了一个主要的IDDM易感基因，称为Iddm/kdp 1，在该地区之间的Mox 2和D11 M16 Mit 46大鼠染色体（Chr）11。KDP等位基因在这个位点的纯合性被证明是必不可少的中度至重度胰岛炎的发展和发病的IDDM。比较映射表明，Iddm/kdp 1的同源物位于人的Chr 3和小鼠的Chr 16，因此将不同于以前报道的IDDM易感基因。（J.Clin.Invest.1997.100：2015-2021.）

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.)