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 SUMMARY Novel 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.
- Abbreviations
- 2’3’-cGAMP
- cyclic GMP-AMP, mammalian cGAMP (tlrl-nacga23)
- 3’3’-cGAMP
- cyclic GMP-AMP, bacterial cGAMP (tlrl-nacga)
- c-di-GMP
- cyclic di-guanylate monophosphate (tlrl-nacdg)
- CDN
- cyclic-di-nucleotide
- FCL
- familial chilblain lupus
- GOF
- gain-of-function
- IFIH1
- interferon induced with helicase C domain 1
- SAVI
- STING-associated vasculopathy with onset in infancy
- SLE
- systemic lupus erythematosus
- SMS
- Singleton-Merten syndrome
- STING
- Stimulator of interferon genes protein
- TMEM173
- transmembrane protein 173
Footnotes
CONFLICT OF INTEREST: M.S. has received honoraria from CSL Behring. S.M. has received honoraria from BMS and Novartis. J.S. has received honoraria from Roche. K.H-J. has received honoraria from Octapharma and Abbvie. A.R. is an Advisory Board Member of ImmunoQure Gmbh. Other authors declare no conflict of interest.