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Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

Alice Lepelley 1 Erika Mina 1 Erika van Nieuwenhove 2, 3, 4 Lise Waumans 2 Sylvie Fraitag 5 Gillian Rice 6 Ashish Dhir 7 Marie-Louise Frémond 1 Mathieu Rodero 1 Luis Seabra 1 Edwin Carter 7 Christine Bodemer 1 Daniela Buhas 8, 9 Bert Callewaert 10 Pascale de Lonlay 11, 1 Lien de Somer 4, 3, 2 David Dyment 12 Fran Faes 10 Lucy Grove 13 Simon Holden 14 Marie Hully 5 Manju Kurian 15 Hugh Mcmillan 16 Kristin Suetens 2 Henna Tyynismaa 17 Stephanie Chhun 18, 11 Timothy Wai 19 Carine Wouters 4, 3, 2 Brigitte Bader- Meunier 1 Yanick Crow 1, 7
Abstract : Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNAhas 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 novodominant-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 ATAD3Ain 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 cellsand patient fibroblastsdepleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
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https://www.hal.inserm.fr/inserm-03297221
Contributor : Alice Lepelley <>
Submitted on : Friday, July 23, 2021 - 11:52:19 AM
Last modification on : Tuesday, September 14, 2021 - 3:37:52 AM

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Alice Lepelley, Erika Mina, Erika van Nieuwenhove, Lise Waumans, Sylvie Fraitag, et al.. Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A. Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (10), pp.e20201560. ⟨10.1084/jem.20201560⟩. ⟨inserm-03297221⟩

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