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-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.

Author affiliation: König, Nadja. Technische Universität Dresden; Alemania

Author affiliation: Fiehn, Christoph. Acura Akutklinik Für Rheumatologie Baden-baden; Alemania

Author affiliation: Wolf, Christine. Technische Universität Dresden; Alemania

Author affiliation: Schuster, Max. Technische Universität Dresden; Alemania

Author affiliation: 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

Author affiliation: Tüngler, Victoria. Technische Universität Dresden; Alemania

Author affiliation: 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

Author affiliation: 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

Author affiliation: Engel, Kerstin. Technische Universität Dresden; Alemania

Author affiliation: Goldbach Mansky, Raphaela. Technische Universität Dresden; Alemania

Author affiliation: Günther, Claudia. National Institutes of Health; Estados Unidos

Author affiliation: Lee Kirsch, Min Ae. Technische Universität Dresden; Alemania

Abstract:

SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi–Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-α initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.

Author affiliation: Tuengler, Victoria. Technische Universität Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Wolfgang, Staroske. Technische Universität Dresden; Alemania

Author affiliation: Kind, Barbara. Technische Universität Dresden; Alemania

Author affiliation: Dobrick, Manuela. Technische Universität Dresden; Alemania

Author affiliation: Kretschmer, Stefanie. Technische Universität Dresden; Alemania

Author affiliation: Schmidt, Franziska. Technische Universität Dresden; Alemania

Author affiliation: Krug, Claudia. Technische Universität Dresden; Alemania

Author affiliation: Lorenz, Mike. Max Planck Institute of Molecular Cell Biology and Genetics; Alemania

Author affiliation: 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. Technische Universität Dresden; Alemania

Author affiliation: Schwille, Petra. Max Planck Institute Of Biochemistry; Alemania

Author affiliation: Lee-Kirsch, Min Ae. Technische Universität Dresden; Alemania