Objectives Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 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-β 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 IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.
- Systemic Lupus Erythematosus
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Handling editor Tore K Kvien
NK and CF contributed equally.
Correction notice This article has been corrected since it was published Online First. The segmentation of the fifth author's name has been corrected.
Contributors NK, CF and MAL-K designed the study. NK, CF, CW, MS, KE and CG performed experiments and analysed data. ECC, VT, HAA and OC performed structural analysis. RG-M provided material and advice. NK and MAL-K wrote the paper. MAL-K supervised the study.
Funding Supported by grants from the Deutsche Forschungsgemeinschaft (LE 1074/3-1 and LE 1074/4-1, to MAL-K; TU 421/1-2 to VT, GU1212/1-1 and GU 1212/1-2 to CG), the Friede Springer Stiftung and the TU Dresden Graduate Academy (great!ipid4all) to MAL-K. OC is a career researcher of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Argentina. The Deep Sequencing Facility of the Biotechnology Center and the Center for Regenerative Therapies Dresden, Technische Universität Dresden, are funded by the Deutsche Forschungsgemeinschaft.
Competing interests None declared.
Ethics approval TU Dresden.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement NK and MAL-K have access to all data and data are available on request.