Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

Abstract

TMEM173 encodes for STING that is a transmembrane protein activated by pathogen or self-derived cytosolic nucleic acids causing its translocation from ER to Golgi, and further to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms causing the poor phenotypegenotype correlation are presently unclear. Here we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and STING-associated vasculopathy with onset in infancy (SAVI) -features; livedo reticularis, nasal septum perforation, facial erythema, bacterial infections and skin vasculitis. Single residue polymorphisms in TMEM173 and an IFIH1 T946 risk allele modify disease presentation in the affected multigeneration family, explaining the varying clinical phenotypes. The G207E mutation causes constitutive activation of inflammation-related pathways in HEK cells, as well as aberrant interferon signature and inflammasome activation in patient PBMCs. Protein-protein interactions further propose impaired cellular trafficking of G207E mutant STING. These findings reveal the molecular landscape of STING and highlight the complex additive effects on the phenotype.\n\nBRIEF SUMMARYNovel gain-of-function mutation in TMEM173, associated with single residue polymorphisms in TMEM173 and IFIH1, causes a distinct clinical phenotype with some shared features of SAVI.