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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Alice Lepelley
  • Erika Della Mina
  • Erika Van Nieuwenhove
  • Lise Waumans
  • Sylvie Fraitag
  • Ashish Dhir
  • Marie-Louise Frémond
  • Mathieu P. Rodero
  • Luis Seabra
  • Edwin Carter
  • Christine Bodemer
  • Daniela Buhas
  • Bert Callewaert
  • Pascale de Lonlay
  • Lien De Somer
  • David A. Dyment
  • Fran Faes
  • Lucy Grove
  • Simon Holden
  • Marie Hully
  • Manju A. Kurian
  • Hugh J. McMillan
  • Kristin Suetens
  • Henna Tyynismaa
  • Stéphanie Chhun
  • Timothy Wai
  • Carine Wouters
  • Brigitte Bader-Meunier
  • Yanick J. Crow


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.

Bibliographical metadata

Original languageEnglish
Article numbere20201560
JournalJournal of Experimental Medicine
Issue number10
Publication statusPublished - 13 Aug 2021