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

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...

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Autores principales: Lin, Bin, Torreggiani, Sofia, Kahle, Dana, Rumsey, Dax G., Wright, Benjamin L., Montes-Cano, Marco A., Silveira, Laura Fernandez, Alehashemi, Sara, Mitchell, Jacob, Aue, Alexander G., Ji, Zheng, Jin, Tengchuan, de Jesus, Adriana A., Goldbach-Mansky, Raphaela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023226/
https://www.ncbi.nlm.nih.gov/pubmed/33833757
http://dx.doi.org/10.3389/fimmu.2021.636225
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author Lin, Bin
Torreggiani, Sofia
Kahle, Dana
Rumsey, Dax G.
Wright, Benjamin L.
Montes-Cano, Marco A.
Silveira, Laura Fernandez
Alehashemi, Sara
Mitchell, Jacob
Aue, Alexander G.
Ji, Zheng
Jin, Tengchuan
de Jesus, Adriana A.
Goldbach-Mansky, Raphaela
author_facet Lin, Bin
Torreggiani, Sofia
Kahle, Dana
Rumsey, Dax G.
Wright, Benjamin L.
Montes-Cano, Marco A.
Silveira, Laura Fernandez
Alehashemi, Sara
Mitchell, Jacob
Aue, Alexander G.
Ji, Zheng
Jin, Tengchuan
de Jesus, Adriana A.
Goldbach-Mansky, Raphaela
author_sort Lin, Bin
collection PubMed
description 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.
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spelling pubmed-80232262021-04-07 Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation Lin, Bin Torreggiani, Sofia Kahle, Dana Rumsey, Dax G. Wright, Benjamin L. Montes-Cano, Marco A. Silveira, Laura Fernandez Alehashemi, Sara Mitchell, Jacob Aue, Alexander G. Ji, Zheng Jin, Tengchuan de Jesus, Adriana A. Goldbach-Mansky, Raphaela Front Immunol Immunology 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. Frontiers Media S.A. 2021-03-22 /pmc/articles/PMC8023226/ /pubmed/33833757 http://dx.doi.org/10.3389/fimmu.2021.636225 Text en Copyright © 2021 Lin, Torreggiani, Kahle, Rumsey, Wright, Montes-Cano, Silveira, Alehashemi, Mitchell, Aue, Ji, Jin, de Jesus and Goldbach-Mansky http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Lin, Bin
Torreggiani, Sofia
Kahle, Dana
Rumsey, Dax G.
Wright, Benjamin L.
Montes-Cano, Marco A.
Silveira, Laura Fernandez
Alehashemi, Sara
Mitchell, Jacob
Aue, Alexander G.
Ji, Zheng
Jin, Tengchuan
de Jesus, Adriana A.
Goldbach-Mansky, Raphaela
Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title_full Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title_fullStr Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title_full_unstemmed Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title_short Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation
title_sort case report: novel savi-causing variants in sting1 expand the clinical disease spectrum and suggest a refined model of sting activation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023226/
https://www.ncbi.nlm.nih.gov/pubmed/33833757
http://dx.doi.org/10.3389/fimmu.2021.636225
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