NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans
NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans
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DOI：
10.2337/diabetes.49.10.1744
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发表时间：
2000-10-01
期刊：
影响因子：
7.7
通讯作者：
Peterson, LB
中科院分区：
文献类型：
--
作者：
Hill, NJ;Lyons, PA;Peterson, LB
对NOD小鼠中b10来源的基因座进行的基因组扫描显示，在1号染色体近端有一个大区域（34 cM）的连锁。该位点被命名为Idd5，包含候选基因包括Il1r1、Il1r2、Stat1、Stat4、Nramp1和Bcl2。在目前的研究中，我们通过开发一系列具有糖尿病抗性的同源小鼠品系，证实了Idd5的存在，并确定Idd5实际上是位于9.4 cm间隔内的两个基因。Idd5.1位于间隔的近1.5 cm部分，包含候选Casp8、Cflar （FLIP）、Cd28和Cd152 （CTLA4）。Idd5.1在人类中与同源的CTLA4/IDDM12位点重叠。Idd5.2位于9.4 cm间隔的远端5.1 cm部分，包含候选基因Nramp1，其在NOD和B10之间具有功能多态性，以及Cmkar2 （CXCR2，白细胞介素[IL]-8受体α）。该分析排除的候选基因包括Ilr1、Ilr2、Zap70、Orch5、Stat1、Stat4、Bcl2、Cmkar4 （CXCR4）和Il10。单独来看，Idd5基因座对糖尿病提供了大量的保护（比亲本频率减少50%），当与另一个抗性基因座（3号染色体上的Idd3）结合时，对糖尿病和胰岛素提供了几乎完全的保护。
A genome scan for B10-derived loci that reduce the frequency of diabetes and insulitis in NOD mice demonstrated a large region (34 cM) of Linkage on the proximal end of chromosome 1. This locus was designated Idd5 and encompassed candidate genes including Il1r1, Il1r2, Stat1, Stat4, Nramp1, and Bcl2. In the current study, we have confirmed the existence of Idd5 by developing a series of congenic mouse strains that are resistant to diabetes and determined that Idd5 is actually two genes located within a 9.4-cM interval. Idd5.1 is in the proximad 1.5-cM portion of the interval and contains the candidates Casp8, Cflar (FLIP), Cd28, and Cd152 (CTLA4). Idd5.1 overlaps the orthologous CTLA4/IDDM12 locus in humans. Idd5.2 is in the distal 5.1-cM portion of the 9.4-cM interval and contains the candidates Nramp1, which has a functional polymorphism between NOD and B10, and Cmkar2 (CXCR2, interleukin [IL]-8 receptor alpha). Candidate genes eliminated by this analysis include Ilr1, Ilr2, Zap70, Orch5, Stat1, Stat4, Bcl2, Cmkar4 (CXCR4), and Il10 . On its own, the Idd5 locus provides a significant amount of protection from diabetes (50% reduction from parental frequency) and when combined with another resistance locus (Idd3 on chromosome 3), provides nearly complete protection from diabetes and insulitis.