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

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dc.contributor.author Lepelley, Alice
dc.contributor.author Della Mina, Erika
dc.contributor.author Van Nieuwenhove, Erika
dc.contributor.author Waumans, Lise
dc.contributor.author Fraitag, Sylvie
dc.contributor.author Rice, Gillian I.
dc.contributor.author Dhir, Ashish
dc.contributor.author Fremond, Marie-Louise
dc.contributor.author Rodero, Mathieu P.
dc.contributor.author Seabra, Luis
dc.contributor.author Carter, Edwin
dc.contributor.author Bodemer, Christine
dc.contributor.author Buhas, Daniela
dc.contributor.author Callewaert, Bert
dc.contributor.author de Lonlay, Pascale
dc.contributor.author De Somer, Lien
dc.contributor.author Dyment, David A.
dc.contributor.author Faes, Fran
dc.contributor.author Grove, Lucy
dc.contributor.author Holden, Simon
dc.contributor.author Hully, Marie
dc.contributor.author Kurian, Manju A.
dc.contributor.author McMillan, Hugh J.
dc.contributor.author Suetens, Kristin
dc.contributor.author Tyynismaa, Henna
dc.contributor.author Chhun, Stephanie
dc.contributor.author Wai, Timothy
dc.contributor.author Wouters, Carine
dc.contributor.author Bader-Meunier, Brigitte
dc.contributor.author Crow, Yanick J.
dc.date.accessioned 2021-11-22T15:52:02Z
dc.date.available 2021-11-22T15:52:02Z
dc.date.issued 2021-10-04
dc.identifier.citation 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
dc.identifier.other PURE: 170528798
dc.identifier.other PURE UUID: 1f73698a-7adc-43e7-8885-ad54afa4c3a1
dc.identifier.other WOS: 000701689800007
dc.identifier.other ORCID: /0000-0002-2493-2422/work/103593753
dc.identifier.uri http://hdl.handle.net/10138/336598
dc.description.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. en
dc.format.extent 23
dc.language.iso eng
dc.relation.ispartof Journal of Experimental Medicine
dc.rights cc_by_nc_sa
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject RECURRENT DE-NOVO
dc.subject AICARDI-GOUTIERES SYNDROME
dc.subject MITOCHONDRIAL-DNA
dc.subject I INTERFERON
dc.subject MEMBRANE-PROTEIN
dc.subject RNASEH2B
dc.subject DUPLICATIONS
dc.subject CHOLESTEROL
dc.subject DYSFUNCTION
dc.subject INDUCTION
dc.subject 3111 Biomedicine
dc.title Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A en
dc.type Article
dc.contributor.organization STEMM - Stem Cells and Metabolism Research Program
dc.contributor.organization Centre of Excellence in Stem Cell Metabolism
dc.contributor.organization Staff Services
dc.contributor.organization Henna Tyynismaa / Principal Investigator
dc.contributor.organization Neuroscience Center
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1084/jem.20201560
dc.relation.issn 0022-1007
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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