ePrints

Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib

Lookup NU author(s): Dr Florian Gothe, Emeritus Professor Drew Rowan, Angela Grainger, Professor Andrew Cant, Professor Mary Slatter, Professor Sophie HambletonORCiD, Dr Desa Lilic

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

© 2019, Springer Science+Business Media, LLC, part of Springer Nature.Mutations in the coiled-coil and DNA-binding domains of STAT1 lead to delayed STAT1 dephosphorylation and subsequently gain-of-function. The associated clinical phenotype is broad and can include chronic mucocutaneous candidiasis (CMC) and/or combined immunodeficiency (CID). We report a case of CMC/CID in a 10-year-old boy due to a novel mutation in the small ubiquitin molecule (SUMO) consensus site at the C-terminal region of STAT1 leading to gain-of-function by impaired sumoylation. Immunodysregulatory features of disease improved after Janus kinase inhibitor (jakinib) treatment. Functional testing after treatment confirmed reversal of the STAT1 hyper-phosphorylation and downstream transcriptional activity. IL-17 and IL-22 production was, however, not restored with jakinib therapy (ruxolitinib), and the patient remained susceptible to opportunistic infection. In conclusion, a mutation in the SUMO consensus site of STAT1 can lead to gain-of-function that is reversible with jakinib treatment. However, full immunocompetence was not restored, suggesting that this treatment strategy might serve well as a bridge to definitive therapy such as hematopoietic stem cell transplant rather than a long-term treatment option.

Publication metadata

Author(s): Al Shehri T, Gilmour K, Gothe F, Loughlin S, Bibi S, Rowan AD, Grainger A, Mohanadas T, Cant AJ, Slatter MA, Hambleton S, Lilic D, Leahy TR

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Immunology

Year: 2019

Volume: 39

Pages: 776-785

Online publication date: 11/09/2019

Acceptance date: 02/09/2019

ISSN (print): 0271-9142

ISSN (electronic): 1573-2592

Publisher: Springer

URL: https://doi.org/10.1007/s10875-019-00687-4

DOI: 10.1007/s10875-019-00687-4

PubMed id: 31512162

Altmetrics

Share