Meas Rithy, Nititham Joanne, Taylor Kimberly E, Maher Stephen, Clairmont Kaylyn, Carufe Kelly E W, Kashgarian Michael, Nottoli Timothy, Cheong Ana, Nagel Zachary D, Gaffney Patrick M, Criswell Lindsey A, Sweasy Joann B
University of Arizona, Tucson.
University of California, San Francisco.
ACR Open Rheumatol. 2022 Sep;4(9):760-770. doi: 10.1002/acr2.11471. Epub 2022 Jun 16.
To determine if single-nucleotide polymorphisms (SNPs) in DNA repair genes are enriched in individuals with systemic lupus erythematosus (SLE) and if they are sufficient to confer a disease phenotype in a mouse model.
Human exome chip data of 2499 patients with SLE and 1230 healthy controls were analyzed to determine if variants in 10 different mismatch repair genes (MSH4, EXO1, MSH2, MSH6, MLH1, MSH3, POLH, PMS2, ML3, and APEX2) were enriched in individuals with SLE. A mouse model of the MSH6 SNP, which was found to be enriched in individuals with SLE, was created using CRISPR/Cas9 gene targeting. Wildtype mice and mice heterozygous and homozygous for the MSH6 variant were then monitored for 2 years for the development of autoimmune phenotypes, including the presence of high levels of antinuclear antibodies (ANA). Additionally, somatic hypermutation frequencies and spectra of the intronic region downstream of the V J558-rearranged J immunoglobulin gene was characterized from Peyer's patches.
Based on the human exome chip data, the MSH6 variant (rs63750897, p.Ser503Cys) is enriched among patients with SLE versus controls after we corrected for ancestry (odds ratio = 8.39, P = 0.0398). Mice homozygous for the MSH6 variant (Msh6 ) harbor significantly increased levels of ANA. Additionally, the Msh6 mice display a significant increase in the infiltration of CD68+ cells (a marker for monocytes and macrophages) into the lung alveolar space as well as apoptotic cells. Furthermore, characterization of somatic hypermutation in these mice reveals an increase in the DNA polymerase η mutational signature.
An MSH6 mutation that is enriched in humans diagnosed with lupus was identified. Mice harboring this Msh6 mutation develop increased autoantibodies and an inflammatory lung disease. These results suggest that the human MSH6 variant is linked to the development of SLE.
确定DNA修复基因中的单核苷酸多态性（SNP）在系统性红斑狼疮（SLE）患者中是否富集，以及它们是否足以在小鼠模型中赋予疾病表型。
分析2499例SLE患者和1230例健康对照的人类外显子芯片数据，以确定10种不同错配修复基因（MSH4、EXO1、MSH2、MSH6、MLH1、MSH3、POLH、PMS2、ML3和APEX2）中的变异在SLE患者中是否富集。使用CRISPR/Cas9基因靶向技术创建了在SLE患者中富集的MSH6 SNP的小鼠模型。然后对野生型小鼠以及MSH6变异的杂合子和纯合子小鼠进行了2年的监测，观察自身免疫表型的发展，包括高水平抗核抗体（ANA）的存在。此外，从派伊尔结中对V J558重排的J免疫球蛋白基因下游内含子区域的体细胞高频突变频率和谱进行了表征。
基于人类外显子芯片数据，在校正祖先因素后，与对照组相比，MSH6变异（rs63750897，p.Ser503Cys）在SLE患者中富集（优势比 = 8.39，P = 0.0398）。MSH6变异纯合子（Msh6）小鼠体内ANA水平显著升高。此外，Msh6小鼠肺肺泡空间中CD68+细胞（单核细胞和巨噬细胞的标志物）以及凋亡细胞的浸润显著增加。此外，对这些小鼠体细胞高频突变的表征显示DNA聚合酶η突变特征增加。
鉴定出一种在诊断为狼疮的人类中富集的MSH6突变。携带这种Msh6突变的小鼠会产生更多自身抗体并患上炎症性肺病。这些结果表明人类MSH6变异与SLE的发展有关。
