Background Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called ...STING-associated vasculopathy with onset in infancy (SAVI). Objectives We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Methods Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. Results Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Conclusions Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
The patients, aged between 5 and 12 years, exhibited the phenotypic variability associated with TMEM173-activating mutations,2-4 with lung disease and systemic inflammation being the major features ...in patient 1 (P1) and patient 3 (P3), while in patient 2 (P2) skin involvement was most prominent (Fig 1; see Supplemental Text and Table E1 in this article's Online Repository at www.jacionline.org). Modest and incomplete downregulation of ISG was recently described in splenic B cells of mice treated with tofacitinib, a JAK1/3 inhibitor, with differential signaling effects suggesting currently poorly understood facets of IFN regulation.9 In this regard, our kinetic ex vivo experiments provide insights into the rapid dynamic changes in IFN signaling secondary to JAK1 blockade.
We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and ...vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes STING-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.
Abstract Objective RASopathies (Noonan syndrome (NS) and Noonan-related syndromes) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat ...sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway (PTPN11, SOS1, RAF, KRAS or NRAS, and SHOC2). Some monogenic conditions are associated with the development of systemic lupus erythematosus (SLE), and a few reports described the association of SLE with NS. We aim to search for a relationship between RASopathy and the development of SLE. Methods We reported for the first time a case of 13-year-old boy with NS with loose anagen hair (NSLAH) resulting from mutation in SHOC2 who developed an autoimmune disorder that fulfilled four American College of Rheumatology (ACR) criteria for the classification of SLE (polyarthritis, pericarditis, antinuclear antibodies, and anti-DNA antibodies). The case report then prompted a literature review by a systematic search for English and French articles on the subjects of RASopathies and SLE that had English abstracts in PubMed from 1966 to 2012. Results We identified seven additional patients with RASopathy and SLE. The male-to-female ratio was 1:1 and age at onset of SLE ranged from 5 to 32 years. The most common features were polyarthritis (7/8 patients), autoimmune cytopenia (4/8 patients), and pericarditis (4/8 patients) while only one patient presented with skin involvement. Conclusion The association of two rare diseases in eight patients suggests that RASopathies may be associated with the development of SLE, which is characterized by a higher male-to-female ratio, a lower rate of skin involvement, and a higher rate of pericarditis than “classic” SLE.
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