@article{e9bbb5d5b7464e3c9b5e82ba040e24ec,
title = "Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A",
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 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.",
keywords = "ATPases Associated with Diverse Cellular Activities/genetics, Child, Child, Preschool, DNA, Mitochondrial/genetics, Female, Genes, Dominant, Humans, Interferons/genetics, Male, Membrane Proteins/genetics, Mitochondrial Proteins/genetics, Mutation, Nucleotidyltransferases/genetics, Scleroderma, Systemic/genetics, Signal Transduction, THP-1 Cells, Young Adult",
author = "Alice Lepelley and Mina, \{Erika Della\} and Nieuwenhove, \{Erika Van\} and Lise Waumans and Sylvie Fraitag and Rice, \{Gillian I.\} and Ashish Dhir and Marie-Louise Fr{\'e}mond and Rodero, \{Mathieu P.\} and Luis Seabra and Edwin Carter and Christine Bodemer and Daniela Buhas and Bert Callewaert and Lonlay, \{Pascale de\} and Somer, \{Lien De\} and Dyment, \{David A.\} and Fran Faes and Lucy Grove and Simon Holden and Marie Hully and Kurian, \{Manju A.\} and McMillan, \{Hugh J.\} and Kristin Suetens and Henna Tyynismaa and St{\'e}phanie Chhun and Timothy Wai and Carine Wouters and Brigitte Bader-Meunier and Crow, \{Yanick J.\}",
note = "Funding Information: Disclosures: E. Van Nieuwenhove reported grants from FWO/ Research Foundation Flanders (SB grant 1S22718N) during the conduct of the study. No other disclosures were reported. Funding Information: Y.J. Crow acknowledges that this project has received funding from the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement 786142), a state subsidy managed by the National Research Agency (France) under the “Investments for the Future” program bearing the reference ANR-10-IAHU-01, and the National Institute for Health Research UK Rare Genetic Disease Research Consortium. The project was supported by MSDAVE-NIR (Devo-Decode Project). E. Van Nieuwenhove acknowledges the Research Foundation Flanders (Fonds voor Wetenschappe-lijk Onderzoek Vlaanderen, grant 1S22716N). B. Callewaert is a Senior Clinical Investigator of the Research Foundation Flanders. Ghent University Hospital, University Hospital Leuven, and H{\^o}pital Universitaire Necker are members of the European Reference Network on Skin Disorders. This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under Marie Sk{\l}odowska-Curie grant agreement 892311 (A. Lepelley). Funding Information: We sincerely thank Jacques Baudier (Institut de Biologie du Developpement de Marseille, Marseille, France) for the generous use of antibodies. The graphical abstract was created with BioRender. Y.J. Crow acknowledges that this project has received funding from the European Research Council under the European Union?s Horizon 2020 research and innovation program (grant agreement 786142), a state subsidy managed by the National Research Agency (France) under the ?Investments for the Future? program bearing the reference ANR-10-IAHU-01, and the National Institute for Health Research UK Rare Genetic Disease Research Consortium. The project was supported by MSDAVENIR (Devo-Decode Project). E. Van Nieuwenhove acknowledges the Research Foundation Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, grant 1S22716N). B. Callewaert is a Senior Clinical Investigator of the Research Foundation Flanders. Ghent University Hospital, University Hospital Leuven, and H?pital Universitaire Necker are members of the European Reference Network on Skin Disorders. This project has received funding from the European Union?s Horizon 2020 research and innovation program under Marie Sk?odowska-Curie grant agreement 892311 (A. Lepelley). Publisher Copyright: {\textcopyright} 2021 Lepelley et al.",
year = "2021",
month = aug,
day = "13",
doi = "10.1084/jem.20201560",
language = "English",
volume = "218",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "10",
}
SDG 3 Good Health and Well-being