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  • Lepelley, Alice; Della Mina, Erika; Van Nieuwenhove, Erika; Waumans, Lise; Fraitag, Sylvie; Rice, Gillian I.; Dhir, Ashish; Fremond, Marie-Louise; Rodero, Mathieu P.; Seabra, Luis; Carter, Edwin; Bodemer, Christine; Buhas, Daniela; Callewaert, Bert; de Lonlay, Pascale; De Somer, Lien; Dyment, David A.; Faes, Fran; Grove, Lucy; Holden, Simon; Hully, Marie; Kurian, Manju A.; McMillan, Hugh J.; Suetens, Kristin; Tyynismaa, Henna; Chhun, Stephanie; Wai, Timothy; Wouters, Carine; Bader-Meunier, Brigitte; Crow, Yanick J. (2021)
    Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
  • Keskitalo, Salla; Haapaniemi, Emma; Einarsdottir, Elisabet; Rajamäki, Kristiina; Heikkilä, Hannele; Ilander, Mette; Pöyhönen, Minna; Morgunova, Ekaterina; Hokynar, Kati; Lagström, Sonja; Kivirikko, Sirpa; Mustjoki, Satu; Eklund, Kari; Saarela, Janna; Kere, Juha; Seppänen, Mikko R. J.; Ranki, Annamari; Hannula-Jouppi, Katariina; Varjosalo, Markku (2019)
    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 polymorphisms in TMEM173 and IFIH1 as likely modifiers of the phenotype.