Novel TMEM173 Mutation and the Role of Disease Modifying Alleles

Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi 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 underlying the variable phenotype-genotype 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 features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in TMEM173 and IFIH1 showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways in vitro, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymo...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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Authors: Zervou MI, Goulielmos GN, Matalliotakis M, Matalliotaki C, Spandidos DA, Eliopoulos E Abstract Adenosine deaminase 2 (ADA2) belongs to the novel family of adenosine deaminase growth factors (ADGFs), which play an important role in tissue development. The deficiency of adenosine deaminase 2 (DADA2) is a recently recognized autosomal recessive autoinflammatory disease, characterized by various systemic vascular and inflammatory manifestations, which is associated with ADA2 mutations. Considering that a recent screening of an international registry of children with systemic primary vasculitis revealed novel a...
Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
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Source: Gut Microbes - Category: Microbiology Authors: Source Type: research
We report a 14 years-old young man with walked unstably, bilateral strephenopodia, severe alopecia and paroxysmal bilateral upper limbs tremor without obvious muscle atrophy. Diagnostic whole-exome sequencing revealed a hemizygote missense mutation c.278 T > A in exon 2 of the GJB1 gene, with lysine at position 93 of the mature protein (p.M93K). This is the first CMT case with alopecia areata reported in the world.
Source: Journal of Clinical Neuroscience - Category: Neuroscience Source Type: research
CONCLUSIONS: The influence of traditional cardiovascular risk factors on cIMT and carotid plaque is similar in RA and SLE. PMID: 31969232 [PubMed - as supplied by publisher]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
Authors: Prevete I, Espinosa G, Bellisai F, Bortoluzzi A, Conti F, Fredi M, Fonseca-Aizpuru EM, García de Viedma V, González-García A, González-León R, Iaccarino L, Iannone F, Marín-Ballvé A, Mitjavila F, Pallarés L, Piga M, Ríos-Garcés R, Suárez S, Tani C, Zanetti A, Ruiz-Irastorza G, Sebastiani GD, Gruppo di Studio SIR sul Lupus Eritematoso Sistemico di recente insorgenza-Early Lupus and Registro Español de pacientes con Lupus Eritematoso Sistémico (RELES), Autoimmune Diseases Study Group (GEAS) Abstract OBJECTIVES: To comp...
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
Authors: Gao N, Cui W, Zhao LM, Li TT, Zhang JH, Pan LL Abstract OBJECTIVES: Takayasu's arteritis (TAK) involves inflammatory vasculitis of large vessels and mainly affects the aorta and its major branches. Abnormal immunity may play a vital role in TAK pathogenesis. Regulatory T cells (Treg cells) are important for peripheral tolerance, but under certain conditions Treg cells can differentiate into Th-like cells that have lost immune suppressive function and promote the development of autoimmune diseases. The role of Th-like Treg cells in TAK is unclear and this study aims to investigate the function of Th-like Tr...
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
This study was conducted to explore the characteristics and risk factors of PE in SLE patients. METHODS: Using the Hospital Information System of Peking Union Medical College Hospital, we conducted a case-control study in SLE patients complicated with PE from January 2012 to December 2018 as the case group, and age-, sex-, and entry-time-matched SLE patients without PE at the ratio of 1:3 as the control group. We explored the risk factors of PE in SLE patients using multivariate logistic regression analyses. RESULTS: A total of 90 cases confirmed with PE from 6994 hospitalised SLE patients were identified and 257 m...
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
CONCLUSIONS: TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease. PMID: 31969218 [PubMed - as supplied by publisher]
Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
Ustekinumab (UST) is an effective treatment for Crohn ’s disease (CD). Here we present two cases of leukocytoclastic vasculitis (LCV) in CD patients after UST induction therapy with a review of the literature.
Source: Gastroenterology - Category: Gastroenterology Authors: Tags: Adverse Events Related to Therapy Source Type: research
Anti-microbial antibodies have been found useful for diagnosis of Crohn ’s disease (CD) and Sjogren’s syndrome (Sjo). These antibodies are also elevated in other autoimmune disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The prevalence of these antibodies in the normal healthy population is unknown. We set t o survey the normal population for these anti-microbial antibodies in comparison with Crohn’s disease and others. Totally 288 blood samples from the donor units of the leukocyte-reduced red blood cells from the American Red Cross were examined...
Source: Gastroenterology - Category: Gastroenterology Authors: Tags: Diagnostics in IBD Source Type: research
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