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

Long-Evans Tokushima Lean(LETL)大鼠具有胰岛素依赖型糖尿病(IDDM)的快速发病、IDDM发病率无性别差异、胰岛β细胞自身免疫破坏、无明显T细胞减少等特点，是理想的人类IDDM动物模型。首次遗传学分析表明MHC连锁基因参与了IDDM的发病机制。到目前为止，由于IDDM在该菌株中的发病率较低(约20%)，其他遗传因素尚未被揭示。我们已经建立了易患糖尿病的LETL大鼠的一个亚系，命名为Komeda糖尿病易感(KDP)大鼠，在220天内表现出100%的胰岛素炎和超过70%的IDDM发病率。在这项研究中，我们首次对KDP大鼠的非MHC IDDM易感基因进行了全基因组扫描，并在大鼠染色体(Chr)11上的Mox2和D11M16Mit46之间的区域发现了一个主要的IDDM易感基因，称为IDDM/kdp1。该基因的纯合性被证明在中到重度胰岛素炎的发生和IDDM的发病中是必不可少的。比较图谱表明，IDDM/kdp1的同源基因位于人Chr 3和小鼠Chr 16上，因此将不同于以前报道的IDDM易感基因。(J.Clin.Invest.1997.100：2015-2021年。)

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.)