Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation

Bin Lin,Benjamin L. Wright,Laura Fernandez Silveira,Sara Alehashemi,Sofia Torreggiani,Jacob Mitchell,Dana Kahle,Dax G. Rumsey,Marco A. Montes-Cano,Adriana A. de Jesus,Alexander G. Aue,Raphaela Goldbach-Mansky,Tengchuan Jin,Zheng Ji

doi:10.3389/fimmu.2021.636225

Abstract

Gain-of-function mutations in STING1 cause the monogenic interferonopathy, SAVI, which presents with early-onset systemic inflammation, cold-induced vasculopathy and/or interstitial lung disease. We identified 5 patients (3 kindreds) with predominantly peripheral vascular disease who harbor 3 novel STING1 variants, p.H72N, p.F153V, and p.G158A. The latter two were predicted by a previous cryo-EM structure model to cause STING autoactivation. The p.H72N variant in exon 3, however, is the first SAVI-causing variant in the transmembrane linker region. Mutations of p.H72 into either charged residues or hydrophobic residues all led to dramatic loss of cGAMP response, while amino acid changes to residues with polar side chains were able to maintain the wild type status. Structural modeling of these novel mutations suggests a reconciled model of STING activation, which indicates that STING dimers can oligomerize in both open and closed states which would obliviate a high-energy 180° rotation of the ligand-binding head for STING activation, thus refining existing models of STING activation. Quantitative comparison showed that an overall lower autoactivating potential of the disease-causing mutations was associated with less severe lung disease, more severe peripheral vascular disease and the absence of a robust interferon signature in whole blood. Our findings are important in understanding genotype-phenotype correlation, designing targeted STING inhibitors and in dissecting differentially activated pathways downstream of different STING mutations.

Highlights

Autoactivating variants in Stimulator of interferon response 2’3’-cyclic GMP–AMP (cGAMP) interactor 1 (STING1, known as TMEM173), the gene that encodes STING (Stimulator of IFN genes) [1,2,3] cause a rare autoinflammatory interferonopathy, STING-associated vasculopathy with onset in infancy (SAVI, OMIM # 615934) [4,5,6]
All patients presented with peripheral vasculopathy (Figures 1A–G), while lung involvement and features of systemic inflammation were more variable between patients
Whole Exome Sequencing (WES) at the age of 5 revealed a de novo heterozygous Stimulator of interferon response cGAMP interactor 1 (STING1) variant, p.G158A, which is not observed in healthy populations from gnomAD database, and she was diagnosed with SAVI

Summary

Introduction

Autoactivating variants in Stimulator of interferon response cGAMP interactor 1 (STING1, known as TMEM173), the gene that encodes STING (Stimulator of IFN genes) [1,2,3] cause a rare autoinflammatory interferonopathy, STING-associated vasculopathy with onset in infancy (SAVI, OMIM # 615934) [4,5,6]. SAVI-causing variants in exons 5, 6 and 7 were so far found in 8 different amino acid residues that lead to STING autoactivation in the absence of ligand-binding [5,6,7,8,9,10,11]. We report 3 novel SAVI-causing mutations in 3 unrelated kindreds, including variant p.H72N, which was disease-causing in a mother and 2 children, and is the first disease-causing gain-offunction (GOF) mutation in the transmembrane linker region of STING [12]. Modeling of previously reported and these novel SAVI mutations extend our current understanding of STING activation involving critical residues that are mutated in the connector helix loop encoded by exon 5, the polymer interface encoded by exon 6 and 7, and the transmembrane linker region encoded by exon 3

Methods

Results

Conclusion