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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)468-472
Seitenumfang5
FachzeitschriftAnnals of the Rheumatic Diseases
Jahrgang76
Ausgabenummer2
PublikationsstatusVeröffentlicht - Feb. 2017
Peer-Review-StatusJa

Externe IDs

researchoutputwizard legacy.publication#75980
researchoutputwizard legacy.publication#78050
researchoutputwizard legacy.publication#78425
Scopus 84984621777
PubMed 27566796
ORCID /0000-0002-4330-1861/work/143782542
ORCID /0000-0003-3486-2824/work/151436578

Schlagworte

Schlagwörter

  • Adult, Blotting, Western, Chilblains/drug therapy, Family, Female, Greece, Humans, Interferon Type I/immunology, Interferon-beta/immunology, Lupus Erythematosus, Cutaneous/drug therapy, Male, Membrane Proteins/genetics, Microscopic Angioscopy, Molecular Docking Simulation, Mutation, Pedigree, Piperidines/therapeutic use, Protein Kinase Inhibitors/therapeutic use, Pyrimidines/therapeutic use, Pyrroles/therapeutic use, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Skin/pathology