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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, Dr Sophie Hambleton, Dr Desa Lilic


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© 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


DOI: 10.1007/s10875-019-00687-4

PubMed id: 31512162


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