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Artículo

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

König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, EmanuelIcon ; Tüngler, Victoria; Alvarez, Hugo ArielIcon ; Chara, OsvaldoIcon ; Engel, Kerstin; Goldbach Mansky, Raphaela; Günther, Claudia; Lee Kirsch, Min Ae
Fecha de publicación: 02/2017
Editorial: B M J Publishing Group
Revista: Annals Of The Rheumatic Diseases
ISSN: 0003-4967
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Medicina Critica y de Emergencia

Resumen

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-â 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 IFNdependent disorders and suggest that JAK inhibition may be of therapeutic value.
Palabras clave: Sting , Familial Chilblain Lupus
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/51987
URL: https://ard.bmj.com/content/76/2/468
DOI: http://dx.doi.org/10.1136/annrheumdis-2016-209841
Colecciones
Articulos(IFLYSIB)
Articulos de INST.FISICA DE LIQUIDOS Y SIST.BIOLOGICOS (I)
Citación
König, Nadja; Fiehn, Christoph; Wolf, Christine; Schuster, Max; Cura Costa, Emanuel; et al.; Familial chilblain lupus due to a gain-of-function mutation in STING; B M J Publishing Group; Annals Of The Rheumatic Diseases; 76; 2; 2-2017; 468-472
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