piperidines and Chilblains

Topics: Chilblains; Humans; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Systemic; Piperidines; Pyrimidines

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.. 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.. 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.. 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.

Topics: Adult; Blotting, Western; Chilblains; Family; Female; Greece; Humans; Interferon Type I; Interferon-beta; Lupus Erythematosus, Cutaneous; Male; Membrane Proteins; Microscopic Angioscopy; Molecular Docking Simulation; Mutation; Pedigree; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Skin