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We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of\n                    <jats:italic>STAT2<\/jats:italic>\n                    that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1220098110","type":"journal-article","created":{"date-parts":[[2013,2,8]],"date-time":"2013-02-08T03:09:43Z","timestamp":1360292983000},"page":"3053-3058","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":252,"title":["STAT2 deficiency and susceptibility to viral illness in humans"],"prefix":"10.1073","volume":"110","author":[{"given":"Sophie","family":"Hambleton","sequence":"first","affiliation":[{"name":"Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;"},{"name":"Pediatric Immunology Service, Great North Children\u2019s Hospital, Newcastle upon Tyne NE1 4LP, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Goodbourn","sequence":"additional","affiliation":[{"name":"Division of Biomedical Sciences, St. George\u2019s, University of London, London SW17 0RE, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan F.","family":"Young","sequence":"additional","affiliation":[{"name":"School of Biology, University of St. Andrews, Fife KY16 9TS, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Dickinson","sequence":"additional","affiliation":[{"name":"Division of Pathway Medicine, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siti M. B.","family":"Mohamad","sequence":"additional","affiliation":[{"name":"Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;"},{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia, 11800 USM Penang, Malaysia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Valappil","sequence":"additional","affiliation":[{"name":"Health Protection Agency, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"McGovern","sequence":"additional","affiliation":[{"name":"Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Cant","sequence":"additional","affiliation":[{"name":"Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom;"},{"name":"Pediatric Immunology Service, Great North Children\u2019s Hospital, Newcastle upon Tyne NE1 4LP, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott J.","family":"Hackett","sequence":"additional","affiliation":[{"name":"Pediatric Immunology Department, Heartlands Hospital, Birmingham B9 5SS, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ghazal","sequence":"additional","affiliation":[{"name":"Division of Pathway Medicine, University of Edinburgh, Edinburgh, EH16 4SB, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil V.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Sciences, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard E.","family":"Randall","sequence":"additional","affiliation":[{"name":"School of Biology, University of St. Andrews, Fife KY16 9TS, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,2,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1099\/vir.0.83391-0","article-title":"Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures","volume":"89","author":"Randall RE","year":"2008","unstructured":"RE Randall, S Goodbourn, Interferons and viruses: An interplay between induction, signalling, antiviral responses and virus countermeasures. 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