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
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
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Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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Source: Clinical and Experimental Rheumatology - Category: Rheumatology Tags: Clin Exp Rheumatol Source Type: research
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Source: Gastroenterology - Category: Gastroenterology Authors: Tags: Adverse Events Related to Therapy Source Type: research
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