Familial chilblain lupus due to a gain-of-function mutation in STING
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
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
Originalsprache | Englisch |
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Seiten (von - bis) | 468-472 |
Seitenumfang | 5 |
Fachzeitschrift | Annals of the Rheumatic Diseases |
Jahrgang | 76 |
Ausgabenummer | 2 |
Publikationsstatus | Veröffentlicht - Feb. 2017 |
Peer-Review-Status | Ja |
Externe IDs
researchoutputwizard | legacy.publication#75980 |
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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