biostudies-literatureLepelley ANational Research AgencyMSDAVENIREuropean Research CouncilEuropean Reference Network on Skin DisordersEuropean Union’s Horizon 2020National Institute for Health Research (NIHR)RosetreesResearch Foundation FlandersMarie Curiee20201560https://www.ebi.ac.uk/biostudies/studies/S-EPMC8374862biostudies-literatureUnknown218(10)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-The Journal of experimental medicineEnhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.PMC8374862RP-2016-07-019M375-F1786142892311CF2 100018-CD2ANR-10-IAHU-01CF2 100018-CD11S22716NBuhas DWai TWouters CCrow YJWaumans LFraitag SDyment DAHully MFaes FCarter Ede Lonlay PRodero MPSeabra LDhir AFremond MLCallewaert BHolden SSuetens KRice GITyynismaa HChhun SGrove LDella Mina EDe Somer LLepelley ABodemer CKurian MAMcMillan HJVan Nieuwenhove EBader-Meunier BfalseEnhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.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-2021-01-01T00:00:00Z2021 Oct2026-06-01T03:05:43.414Z2025-04-05T19:57:48.125ZS-EPMC83748623438765110.1084/jem.20201560