Skip to content

Research at St Andrews

STAT2 deficiency and susceptibility to viral illness in humans

Research output: Contribution to journalArticlepeer-review

DOI

Author(s)

Sophie Hambleton, Stephen Goodbourn, Dan Frushard Young, Paul Dickinson, Siti M. B. Mohamad, Manoj Valappil, Naomi McGovern, Andrew J. Cant, Scott J. Hackett, Peter Ghazal, Neil V. Morgan, Richard Edward Randall

School/Research organisations

Abstract

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.

Close

Details

Original languageEnglish
Pages (from-to)3053-3058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
Publication statusPublished - 19 Feb 2013

    Research areas

  • TLR3 DEFICIENCY, IFN-BETA, INBORN-ERRORS, measles vaccine, TARGETED DISRUPTION, SIGNALING PATHWAY, rare diseases, ALPHA/BETA-INTERFERON, V-PROTEIN, VIRUS ENCEPHALITIS, HERPES-SIMPLEX ENCEPHALITIS, viruses, HOST-DEFENSE

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Genetic lesions of type I interferon signalling in human antiviral immunity

    Duncan, C. J. A., Randall, R. E. & Hambleton, S., Jan 2021, In: Trends in Genetics. 37, 1, p. 46-58 13 p.

    Research output: Contribution to journalReview articlepeer-review

  2. Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells

    Holthaus, D., Vasou, A., Bamford, C., Andrejeva, J., Paulus, C., Randall, R. E., McLauchlan, J. & Hughes, D. J., 22 Jun 2020, In: The Journal of Immunology. 11 p., ji1901472.

    Research output: Contribution to journalArticlepeer-review

  3. Innate intracellular antiviral responses restrict the amplification of defective virus genomes of parainfluenza virus type 5

    Wignall-Fleming, E. B., Vasou, A., Young, D., Short, J. A. L., Hughes, D. J., Goodbourn, S. & Randall, R. E., 16 Jun 2020, In: Journal of Virology. 94, 13, 15 p., 00246-20.

    Research output: Contribution to journalArticlepeer-review

  4. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

    Duncan, C. J. A., Thompson, B. J., Chen, R., Rice, G. I., Gothe, F., Young, D. F., Lovell, S. C., Shuttleworth, V. G., Brocklebank, V., Corner, B., Skelton, A. J., Bondet, V., Coxhead, J., Duffy, D., Fourrage, C., Livingston, J. H., Pavaine, J., Cheesman, E., Bitetti, S., Grainger, A. & 18 others, Acres, M., Innes, B. A., Mikulasova, A., Sun, R., Hussain, R., Wright, R., Wynn, R., Zarhrate, M., Zeef, L. A. H., Wood, K., Hughes, S. M., Harris, C. L., Engelhardt, K. R., Crow, Y. J., Randall, R. E., Kavanagh, D., Hambleton, S. & Briggs, T. A., 13 Dec 2019, In: Science Immunology. 4, 42, eaav7501.

    Research output: Contribution to journalArticlepeer-review

  5. Analysis of paramyxovirus transcription and replication by high-throughput sequencing

    Wignall-Fleming, E. B., Hughes, D. J., Vattipally, S., Modha, S., Goodbourn, S., Davison, A. J. & Randall, R. E., 13 Aug 2019, In: Journal of Virology. 93, 17, 17 p., e00571-19.

    Research output: Contribution to journalArticlepeer-review

Related by journal

  1. Proceedings of the National Academy of Sciences of the United States of America (Journal)

    Michael Martin Nevels (Guest editor)

    Jul 2016 → …

    Activity: Publication peer-review and editorial work typesEditor of research journal

  2. Proceedings of the National Academy of Sciences of the United States of America (Journal)

    Oscar Eduardo Gaggiotti (Member of editorial board)

    1 Jan 2013 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  3. Proceedings of the National Academy of Sciences of the United States of America (Journal)

    Terry K Smith (Member of editorial board)

    2012 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  4. Proceedings of the National Academy of Sciences of the United States of America (Journal)

    Terry K Smith (Member of editorial board)

    2008 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  5. Proceedings of the National Academy of Sciences of the United States of America (Journal)

    Gareth Brian Miles (Reviewer)

    2006 → …

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

Related by journal

  1. A TDDFT investigation of the Photosystem II reaction center: Insights into the precursors to charge separation

    Kavanagh, M. A., Karlsson, J. K. G., Colburn, J. D., Barter, L. M. C. & Gould, I. R., 18 Aug 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 33, p. 19705-19712 8 p.

    Research output: Contribution to journalArticlepeer-review

  2. Acute social isolation alters neurogenomic state in songbird forebrain

    George, J., Bell, Z., Condliffe, D., Doher, K., Abaurrea, T., Spencer, K., Leitao, A., Gahr, M., Hurd, P. & Clayton, D. F., 22 Sep 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 38, p. 23311-23316

    Research output: Contribution to journalArticlepeer-review

  3. An evolutionary switch from sibling rivalry to sibling cooperation, caused by a sustained loss of parental care

    Rebar, D., Bailey, N. W., Jarrett, B. J. M. & Kilner, R. M., 4 Feb 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 5, p. 2544-2550 7 p.

    Research output: Contribution to journalArticlepeer-review

  4. Coastal heritage, global climate change, public engagement, and citizen science

    Dawson, T., Hambly, J., Kelley, A., Lees, W. & Miller, S., 14 Apr 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 15, p. 8280-8286

    Research output: Contribution to journalArticlepeer-review

  5. Electronically driven spin-reorientation transition of the correlated polar metal Ca3Ru2O7

    Markovic, I., Watson, M. D., Clark, O. J., Mazzola, F., Abarca Morales, E., Hooley, C., Rosner, H., Polley, C. M., Balasubramanian, T., Mukherjee, S., Kikugawa, N., Sokolov, D. A., Mackenzie, A. & King, P. D. C., 7 Jul 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 27, p. 15524-15529 6 p.

    Research output: Contribution to journalArticlepeer-review

ID: 53493644

Top