Familial chilblain lupus due to a gain-of-function mutation in STING. Issue 2 (26th August 2016)

• Record Type: Journal Article
• Authors: König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; Tüngler, Victoria; Alvarez, Hugo Ariel; Chara, Osvaldo; Engel, Kerstin; Goldbach-Mansky, Raphaela; Günther, Claudia; Lee-Kirsch, Min Ae
• Is Part Of: Annals of the rheumatic diseases. Volume 76:Issue 2(2017)
• Page Start: 468
• Page End: 472
• Publication Date: 2016-08-26
• Subjects: Autoimmunity -- Inflammation -- Cytokines -- Systemic Lupus Erythematosus; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2016-209841
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : 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.