4 years ago

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations [Genetics]

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations [Genetics]
Paul J. McLaren, Laurent Kaiser, Istvan Bartha, Thomas Junier, David Longchamp, Dominique Garcin, Samuel Cordey, Martin Stocker, Klara M. Posfay–Barbe, Stephanie Anchisi, Thomas Riedel, Amalio Telenti, Caroline Tapparel, Jacques Fellay, Luregn J. Schlapbach, Samira Asgari, Genevieve Mottet–Osman, Christian Hammer, Deborah Long, Tony Kenna, Andreas Schibler

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

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