Familial chilblain lupus due to a gain-of-function mutation in STING
Familial chilblain lupus due to a gain-of-function mutation in STING
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DOI：
10.1136/annrheumdis-2016-209841
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发表时间：
2017-02-01
影响因子：
27.4
通讯作者：
Lee-Kirsch, Min Ae
中科院分区：
文献类型：
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作者：
Konig, Nadja;Fiehn, Christoph;Lee-Kirsch, Min Ae
目的家族性冻疮性狼疮是一种单基因型皮肤红斑狼疮，由核酸酶TREXI或SAMHD 1的功能缺失突变引起。在一个没有TREX 1或SAMHD 1突变的家庭中，我们试图确定致病基因和潜在的疾病病理。方法采用外显子组测序进行疾病基因鉴定。通过同源建模和对接模拟进行结构分析。使用IFN-13报告子和蛋白质印迹法在用STING cDNA转染的细胞中评估I型干扰素（IFN）活化。在患者血液中的IFN签名，在托法替尼治疗的IFN刺激genes.Results的RT-PCR测定在一个多代家庭与5名成员受冻疮狼疮，我们确定了杂合突变STING，在胞质DNA传感通路的信号分子。结构和功能分析表明，突变体STING在其配体cGAMP不存在的情况下增强同源二聚化，导致组成型I型IFN活化。治疗两个受影响的家庭成员与Janus激酶（JAK）抑制剂tofacitinib导致了显着的抑制IFN significant.Conclusions杂合子获得性功能突变STING可以导致家族性冻疮狼疮。这些发现扩展了I型IFN依赖性疾病的遗传谱，并表明JAK抑制可能具有治疗价值。
Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREXI or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology.Methods Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-13 reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.Results In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature.Conclusions A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.