A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).

2.50
Hdl Handle:
http://hdl.handle.net/11287/620572
Title:
A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).
Authors:
Russell, M. A.; Pigors, M.; Houssen, M.E.; Manson, A.; Kelsell, D.; Longhurst, H.; Morgan, Noel
Abstract:
Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).
Citation:
A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID). 2017 Clin. Immunol.
Publisher:
Elsevier
Journal:
Clinical immunology
Issue Date:
24-Nov-2017
URI:
http://hdl.handle.net/11287/620572
DOI:
10.1016/j.clim.2017.11.007
PubMed ID:
29180260
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S1521-6616(17)30691-5
Type:
Journal Article
Language:
en
ISSN:
1521-7035
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorRussell, M. A.en
dc.contributor.authorPigors, M.en
dc.contributor.authorHoussen, M.E.en
dc.contributor.authorManson, A.en
dc.contributor.authorKelsell, D.en
dc.contributor.authorLonghurst, H.en
dc.contributor.authorMorgan, Noelen
dc.date.accessioned2017-12-18T14:38:11Z-
dc.date.available2017-12-18T14:38:11Z-
dc.date.issued2017-11-24-
dc.identifier.citationA novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID). 2017 Clin. Immunol.en
dc.identifier.issn1521-7035-
dc.identifier.pmid29180260-
dc.identifier.doi10.1016/j.clim.2017.11.007-
dc.identifier.urihttp://hdl.handle.net/11287/620572-
dc.description.abstractCommon variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S1521-6616(17)30691-5en
dc.rightsArchived with thanks to Clinical immunology (Orlando, Fla.)en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleA novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).en
dc.typeJournal Articleen
dc.identifier.journalClinical immunologyen
dc.type.versionIn press (epub ahead of print)en

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