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

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Lepelley , A , Della Mina , E , Van Nieuwenhove , E , Waumans , L , Fraitag , S , Rice , G I , Dhir , A , Fremond , M-L , Rodero , M P , Seabra , L , Carter , E , Bodemer , C , Buhas , D , Callewaert , B , de Lonlay , P , De Somer , L , Dyment , D A , Faes , F , Grove , L , Holden , S , Hully , M , Kurian , M A , McMillan , H J , Suetens , K , Tyynismaa , H , Chhun , S , Wai , T , Wouters , C , Bader-Meunier , B & Crow , Y J 2021 , ' Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A ' , Journal of Experimental Medicine , vol. 218 , no. 10 , 20201560 . https://doi.org/10.1084/jem.20201560

Title: Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A
Author: 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.
Contributor organization: STEMM - Stem Cells and Metabolism Research Program
Centre of Excellence in Stem Cell Metabolism
Staff Services
Henna Tyynismaa / Principal Investigator
Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Date: 2021-10-04
Language: eng
Number of pages: 23
Belongs to series: Journal of Experimental Medicine
ISSN: 0022-1007
DOI: https://doi.org/10.1084/jem.20201560
URI: http://hdl.handle.net/10138/336598
Abstract: 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.
3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by_nc_sa
Usage restriction: openAccess
Self-archived version: publishedVersion

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