Date: Sunday, November 8, 2020
Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function (GOF) mutations in STING1/TMEM173 that encodes stimulator of interferon genes, STING, a key mediator in the cytosolic DNA sensing pathway that drives the synthesis of type-I interferons. We report 3 novel SAVI-causing mutations that all lead to STING auto-activation in heterozygosity; 2 mutations occurred de novo and are located in the connector loop domain of STING, and one SAVI-causing mutation was present in 3 affected family members (autosomal-dominant transmission by mother) and is located in the transmembrane linker region.
Methods: All patients were clinically evaluated and studied under an institutional review board (IRB) approved protocol (NCT02974595). To investigate the autoactivating potential of these novel mutations, mutant STING constructs with the respective mutations were transfected into HEK293T cells. IFNB1 reporter activation was measured, and interferon-response gene signatures were measured from whole blood and peripheral blood mononuclear cells (PBMC) RNA samples from patients and their family members.
Results: We identified 3 novel SAVI-causing mutations, p.G158A, or p.F153V occurred de novo and p.H72N was present in 3 symptomatic family members. All patients developed disease in childhood (age at onset 2 months-4 years) and experienced peripheral vasculopathy with chilblains in 4 and erythematous-purple discoloration of the extremities and nasal septal perforation in one; mild lung disease was present only in two patients (p.H72N and p.G158A). None of the patients received chronic steroid treatment or DMARDs, 3 were treated with baricitinib. In an IFNB1 luciferase reporter assay all 3 mutant STING constructs were auto-activating in the absence of cGAMP ligand consistent with previously reported SAVI-causing GOF mutations. Additional mutations of H72 into K, R, D, L, Q, or F, all lead to loss-of-function or partial loss-of-function, indicating the importance of H72 in maintaining the STING structure. Structural modeling reveals that H72 lies in the “arm” restraining the ligand-binding domain, and the H72N mutation partly relieves this restrain and allows the ligand-biding domain to rotate, thus leading to auto-activation. The other 6 mutations on the H72 residue may strongly destabilize this supporting arm and lead to an ill-structured STING dimer, which results in loss-of-function. In contrast to previously reported SAVI patients, patients with the H72N and G158A mutations had a normal interferon scores in the whole blood RNA samples but were positive in PBMC samples.
Conclusion: We identified 3 novel SAVI-causing variants, that all confer a GOF in an IFNB1 luciferase reporter assay. Two mutations, p.F153V and p.G158A, in the connector loop were predicted to be activating by a recent STING Cryo-EM structural model. The H72N is the first mutation in the transmembrane linker region, thus revealing a novel important region that controls STING activation. The absence of an elevated interferon signature in whole blood but presence in PBMCs needs further investigation, but points to the need to evaluate PBMCs in some patients.
To cite this abstract in AMA style:Lin B, Kahle D, Almeida de Jesus A, Torreggiani S, Mitchell J, Aue A, Ji Z, Jin T, Goldbach-Mansky R. Novel STING1 Mutations Including in the Transmembrane Linker Region Cause STING-associated Vasculopathy with Onset in Infancy (SAVI) [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/novel-sting1-mutations-including-in-the-transmembrane-linker-region-cause-sting-associated-vasculopathy-with-onset-in-infancy-savi/. Accessed February 28, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-sting1-mutations-including-in-the-transmembrane-linker-region-cause-sting-associated-vasculopathy-with-onset-in-infancy-savi/