A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID)
Elsevier for Clinical Immunology Society
© 2017 Elsevier Inc. All rights reserved.
Reason for embargo
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 comorbidities. 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 CVIDassociated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).
We gratefully acknowledge the Mission Sector of the Egyptian Ministry of Higher Education (Arab Republic of Egypt) who provided funding for Maha E. Houssen to work as a visiting postdoctoral fellow at the University of Exeter (March 2016-September 2016). This work was also supported by Diabetes UK (grant: 15/0005156).
This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.
Published online 24 November 2017