Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Journal of Experimental Medicine Year : 2021

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

Lise Waumans
Gillian Rice
Ashish Dhir
Edwin Carter
Bert Callewaert
Fran Faes
Simon Holden
Marie Hully
Manju Kurian
Hugh Mcmillan
Kristin Suetens


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 α 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.
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Dates and versions

hal-03736663 , version 1 (23-07-2021)
hal-03736663 , version 2 (12-04-2022)
hal-03736663 , version 3 (17-08-2023)
hal-03736663 , version 4 (07-09-2023)


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Alice Lepelley, Erika Della 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, 2021, 218 (10), pp.e20201560. ⟨10.1084/jem.20201560⟩. ⟨hal-03736663v4⟩
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