STAT2 deficiency and susceptibility to viral illness in humans

Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-02, Vol.110 (8), p.3053-3058
Main Authors: Hambleton, Sophie, Goodbourn, Stephen, Young, Dan F., Dickinson, Paul, Mohamad, Siti M. B., Valappil, Manoj, McGovern, Naomi, Cant, Andrew J., Hackett, Scott J., Ghazal, Peter, Morgan, Neil V., Randall, Richard E.
Format: Article
Language:English
Subjects:
Antivirals
Base Sequence
Biological Sciences
Cells, Cultured
Cellular immunity
Child, Preschool
DNA Primers
Female
Fibroblasts
Genes
Genetic disorders
Genetic Predisposition to Disease
Humans
Immunization
Infections
Infectious diseases
Interferon
Interferon Type I - metabolism
Interferons
Introns
Measles
Mutation
Oligonucleotide Array Sequence Analysis
Pedigree
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
STAT2 Transcription Factor - genetics
Vaccination
Viral infections
Virus Diseases - genetics
Virus Diseases - metabolism
Viruses
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Summary:Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. 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 STAT2 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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1220098110