biostudies-literatureUnknown114(31)Asgari SViral 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-?, 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.Proceedings of the National Academy of Sciences of the United States of America8342-8347https://www.ebi.ac.uk/biostudies/studies/S-EPMC5547624biostudies-literatureSevere viral respiratory infections in children with IFIH1 loss-of-function mutations.PMC5547624Long DSchibler APosfay-Barbe KMBartha IMcLaren PJTapparel CGarcin DHammer CRiedel TMottet-Osman GLongchamp DTelenti AFellay JKenna TSchlapbach LJJunier TKaiser LAsgari SCordey SAnchisi SStocker MfalseSevere viral respiratory infections in children with IFIH1 loss-of-function mutations.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-?, 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.2017-01-01T00:00:00Z2017 Aug2021-02-19T11:55:10Z2019-03-27T02:52:55ZS-EPMC55476242871693510.1073/pnas.1704259114