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.BRIEF 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.

Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells

“…In order to decipher the origin of the chronic activation in patients' T cells, we used a custom gene panel (50 genes linked to immune signaling and inflammasome activation) with Nanostring nCounter (25) to screen for gene expression profiles in the patients' peripheral blood mononuclear (PBMC) cells ex vivo. Both patients had a marked upregulation of genes related to both type 1 and type 2 interferon, NFkB, and JAK-STAT signaling (Fig 2C).…”

“…Also five housekepping genes were included in the analysis. Further details of the code set, hybridization, scanning and data analysis are described elsewhere (25). (54).…”

“…The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08. 25.21262015 doi: medRxiv preprint…”

IFN Regulatory Factor 3 in Health and Disease

“…STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory interferonopathy (138). In SAVI, the TMEM173 gene encoding STING is mutated (N153S) so that mononuclear cells, fibroblasts, and endothelial cells exhibit heightened constitutive activation of STING (139,140). This hyperactivated STING gives rise to heightened activation of IRF3 and production of IFN-b.…”

Analysis of mRNA-miRNA-lncRNA differential expression in prediabetes/type 2 diabetes mellitus patients as potential players in insulin resistance

“…STING is a transmembrane protein triggered by cytosolic self-derived nucleic acids and is encoded by TMEM173 . Most of TMEM173 variants result in JAK/STAT pathway-mediated INF production, which is involved in a variety of inflammatory disorders ( 15 ). Additionally, TMEM173 is involved in oxidative stress and autophagy ( 16 ), both of which are strongly related to insulin signaling.…”