Gene

Janus kinase

Engineering

Innate immune system

Pathology

Aerospace engineering

Antibody

Immunology

Lupus erythematosus

Interferon

Systemic lupus erythematosus

Stimulator of interferon genes

Rheumatoid arthritis

Cytokine

Tofacitinib

Disease

Sting

Mutation

Genetics

Medicine

Biology

Immune system

Annals of the Rheumatic Diseases

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.

Familial chilblain lupus due to a gain-of-function mutation in STING