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Enhanced 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 sug...

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Autores principales: Lepelley, Alice, Della Mina, Erika, Van Nieuwenhove, Erika, Waumans, Lise, Fraitag, Sylvie, Rice, Gillian I., Dhir, Ashish, Frémond, 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, Stéphanie, Wai, Timothy, Wouters, Carine, Bader-Meunier, Brigitte, Crow, Yanick J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862/
https://www.ncbi.nlm.nih.gov/pubmed/34387651
http://dx.doi.org/10.1084/jem.20201560
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author Lepelley, Alice
Della Mina, Erika
Van Nieuwenhove, Erika
Waumans, Lise
Fraitag, Sylvie
Rice, Gillian I.
Dhir, Ashish
Frémond, 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, Stéphanie
Wai, Timothy
Wouters, Carine
Bader-Meunier, Brigitte
Crow, Yanick J.
author_facet Lepelley, Alice
Della Mina, Erika
Van Nieuwenhove, Erika
Waumans, Lise
Fraitag, Sylvie
Rice, Gillian I.
Dhir, Ashish
Frémond, 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, Stéphanie
Wai, Timothy
Wouters, Carine
Bader-Meunier, Brigitte
Crow, Yanick J.
author_sort Lepelley, Alice
collection PubMed
description 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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spelling pubmed-83748622022-04-04 Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A Lepelley, Alice Della Mina, Erika Van Nieuwenhove, Erika Waumans, Lise Fraitag, Sylvie Rice, Gillian I. Dhir, Ashish Frémond, 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, Stéphanie Wai, Timothy Wouters, Carine Bader-Meunier, Brigitte Crow, Yanick J. J Exp Med Brief Definitive Report 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. Rockefeller University Press 2021-08-13 /pmc/articles/PMC8374862/ /pubmed/34387651 http://dx.doi.org/10.1084/jem.20201560 Text en © 2021 Lepelley et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Lepelley, Alice
Della Mina, Erika
Van Nieuwenhove, Erika
Waumans, Lise
Fraitag, Sylvie
Rice, Gillian I.
Dhir, Ashish
Frémond, 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, Stéphanie
Wai, Timothy
Wouters, Carine
Bader-Meunier, Brigitte
Crow, Yanick J.
Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title_full Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title_fullStr Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title_full_unstemmed Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title_short Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A
title_sort enhanced cgas-sting–dependent interferon signaling associated with mutations in atad3a
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862/
https://www.ncbi.nlm.nih.gov/pubmed/34387651
http://dx.doi.org/10.1084/jem.20201560
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