Familiärer Chilblain Lupus durch eine aktivierende Mutation in STING

FIEHN, CHRISTOPH; TÜNGLER VICTORIA; CURA COSTA, EMANUEL; CHRISTINE WOLF; GOLDBACH-MANSKY, RAPHAELA; ALVAREZ HUGO ARIEL; CLAUDIA GÜNTHER; KÖNIG, NADJA; SCHUSTER, MAX; CHARA OSVALDO; LEE-KIRSCH MIN AE

Hamburgo

Congreso; Jahrestagung der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ); 2016

Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ)

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.