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Clin Immunol. 2018 Feb;187:132-136. doi: 10.1016/j.clim.2017.11.007. Epub 2017 Nov 24.

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

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter, Exeter, UK. Electronic address: m.russell@exeter.ac.uk.
2
Centre for Cell Biology & Cutaneous Research, Blizard Institute, Queen Mary University of London, UK.
3
Institute of Biomedical and Clinical Science, University of Exeter, Exeter, UK; Biochemistry Department, Faculty of Pharmacy, Damanhour University, Egypt.
4
Barts Health NHS Trust, London, UK.
5
Institute of Biomedical and Clinical Science, University of Exeter, Exeter, UK.

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).

KEYWORDS:

CVID; Common variable immunodeficiency; Hypogammaglobulinemia; STAT3; Whole exome sequencing

PMID:
29180260
DOI:
10.1016/j.clim.2017.11.007

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