Mutation of POLB causes lupus in mice.
Mutation of POLB causes lupus in mice.
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DOI：
10.1016/j.celrep.2013.12.017
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发表时间：
2014-01-16
期刊：
影响因子：
8.8
通讯作者：
Sweasy JB
中科院分区：
文献类型：
--
作者：
Senejani AG;Liu Y;Kidane D;Maher SE;Zeiss CJ;Park HJ;Kashgarian M;McNiff JM;Zelterman D;Bothwell AL;Sweasy JB
先前的全基因组关联研究（GWAS）的复制研究表明，与POLB基因相关的单核苷酸多态性（SNP）与系统性红斑狼疮（SLE）相关。该SNP与POLB表达降低（Pol β）相关。为了确定Pol β活性降低是否导致SLE，我们构建了编码具有缓慢DNA聚合酶活性的酶的POLB小鼠模型。Pol β是碱基切除修复（BER）途径中的关键酶。我们发现，表达这种亚型POLB等位基因的小鼠发生与SLE非常相似的自身免疫性病理。值得注意的是，来自POL BY265 C/C小鼠的免疫球蛋白重链接头具有较短的长度，并且体细胞超突变显著增加。这些结果表明，免疫多样性产生期间Pol β活性降低导致小鼠狼疮样疾病，并表明人类Pol β表达降低是SLE的潜在原因。
A replication study of a previous genome-wide association study (GWAS) suggested that a single nucleotide polymorphism (SNP) linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased POLB expression (Pol β). To determine if decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. Pol β is a key enzyme in the base excision repair (BER) pathway.. We show that mice expressing this hypomorphic POLB allele develop autoimmune pathology strongly resembling SLE. Of note, the immunoglobulin heavy chain junctions from the POL BY265C/C mice have shorter lengths, and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.
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