Familial chilblain lupus due to a gain-of-function mutation in STING
| Autor: | Kerstin Engel, Christine Wolf, Claudia Günther, Max Schuster, Victoria Tüngler, Christoph Fiehn, Hugo Álvarez, N. König, Osvaldo Chara, Raphaela Goldbach-Mansky, Emanuel Cura Costa, Min Ae Lee-Kirsch |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Mutant Medicina Clínica medicine.disease_cause Autoimmunity Microscopic Angioscopy 0302 clinical medicine Piperidines Interferon Lupus Erythematosus Cutaneous Immunology and Allergy Exome sequencing Skin Greece Reverse Transcriptase Polymerase Chain Reaction Familial chilblain lupus Disease gene identification Pedigree Chilblains Molecular Docking Simulation Interferon Type I Female Medicina Critica y de Emergencia medicine.drug Adult CIENCIAS MÉDICAS Y DE LA SALUD Immunology Blotting Western Biology Real-Time Polymerase Chain Reaction General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Rheumatology medicine Humans Family Pyrroles Protein Kinase Inhibitors 030203 arthritis & rheumatology Tofacitinib Membrane Proteins Interferon-beta Sting 030104 developmental biology Pyrimidines Mutation Janus kinase STING |
| Popis: | 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. Fil: König, Nadja. Technische Universität Dresden; Alemania Fil: Fiehn, Christoph. Acura Akutklinik Für Rheumatologie Baden-baden; Alemania Fil: Wolf, Christine. Technische Universität Dresden; Alemania Fil: Schuster, Max. Technische Universität Dresden; Alemania Fil: Cura Costa, Emanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina Fil: Tüngler, Victoria. Technische Universität Dresden; Alemania Fil: Alvarez, Hugo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina Fil: Engel, Kerstin. Technische Universität Dresden; Alemania Fil: Goldbach Mansky, Raphaela. Technische Universität Dresden; Alemania Fil: Günther, Claudia. National Institutes of Health; Estados Unidos Fil: Lee Kirsch, Min Ae. Technische Universität Dresden; Alemania |
| Databáze: | OpenAIRE |
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