The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes.
The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes.
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DOI：
10.1073/pnas.98.4.1787
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发表时间：
2001-02
影响因子：
11.1
通讯作者：
L. Morel;K. Blenman;B. Croker;E. Wakeland
中科院分区：
文献类型：
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作者：
L. Morel;K. Blenman;B. Croker;E. Wakeland
在多项人类研究中，主要的小鼠系统性红斑狼疮（SLE）易感基因座Sle 1与SLE易感性相关的染色体区域同线。同源分析表明，Sle1打破了对染色质的耐受性，这是完全疾病诱导的必要步骤，可以被特定的修饰基因座抑制。在本研究中，我们的精细定位分析的位置SLE 1已确定，在此同源间隔内的三个位点，称为SLE 1A，SLE 1B，和SLE 1C，可以独立地导致染色质的耐受性损失。每一种都显示出血清学和细胞特征的独特特征，T和B细胞功能分别受到Sle1a和Sle1B的影响更大。然而，Sle 1与其他易感基因座的上位性相互作用导致严重肾炎不能单独由这三个基因座来解释，这表明存在一个额外的基因座，称为Sle 1d。这些研究结果表明，由Sle 1基因组间隔引起的有效自身免疫表型反映了四个独立易感基因的综合影响。这种水平的遗传复杂性，结合其他系统中的类似发现，支持了许多复杂性状基因座反映具有相关功能的连锁基因簇中多态性影响的可能性。
The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin. Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions.