Xu Z, Xu J, Ju J, Morel L
Department of Immunology, Weifang Medical University, Weifang, China.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
Genes Immun. 2017 Sep;18(3):111-117. doi: 10.1038/gene.2017.8. Epub 2017 May 11.
Our previous study uncovered that the overlapping region of murine lupus susceptibility Sle2c1rec1a and Sle2c1rec1d subloci is strongly associated with lymphadenopathy and systemic autoimmunity. In order to identify the specific candidate gene, we generated a novel shorter recombinant, named as Sle2c1re1d1 (rec1d1), from Sle2c1rec1d sublocus (rec1d). The rec1d1 interval corresponds precisely to the overlapping region of Sle2c1rec1a and Sle2c1rec1d subloci. Functionally, this rec1d1 sublocus showed a strong epistatic interaction with lpr, similar to that seen with Sle2c1rec1a or.Sle2c1rec1d. The Skint6 gene in the red1d1 interval was identified to have a point mutation, which inserts a premature stop codon and converts the membrane Skint6 protein into a truncated secretory peptide. However, other protein-coding genes in the rec1d1 interval have no mutation in exon sequence. The heterozygous rec1d1 interval in B6.lpr demonstrates exacerbated autoimmunity. For example, non-hematopoietic stem cell-derived cells of the B6.Sle2c1rec1d1.lpr mice promote T-cell proliferation in vivo. These findings led us to conclude that the Skint6 variant in the rec1d1 interval is the most likely causative gene of mouse lupus.
我们之前的研究发现，小鼠狼疮易感性Sle2c1rec1a和Sle2c1rec1d亚位点的重叠区域与淋巴结病和系统性自身免疫密切相关。为了确定具体的候选基因，我们从Sle2c1rec1d亚位点（rec1d）产生了一种新的较短重组体，命名为Sle2c1re1d1（rec1d1）。rec1d1区间精确对应于Sle2c1rec1a和Sle2c1rec1d亚位点的重叠区域。在功能上，这个rec1d1亚位点与lpr表现出强烈的上位性相互作用，类似于Sle2c1rec1a或Sle2c1rec1d所见。red1d1区间的Skint6基因被鉴定存在一个点突变，该突变插入了一个提前终止密码子，将膜结合的Skint6蛋白转化为截短的分泌肽。然而，rec1d1区间的其他蛋白质编码基因在外显子序列中没有突变。B6.lpr中的杂合rec1d1区间表现出加剧的自身免疫。例如，B6.Sle2c1rec1d1.lpr小鼠的非造血干细胞来源细胞在体内促进T细胞增殖。这些发现使我们得出结论，rec1d1区间的Skint6变体是小鼠狼疮最可能的致病基因。
