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- Title
Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib.
- Authors
Al Shehri, Tariq; Gilmour, Kimberly; Gothe, Florian; Loughlin, Sam; Bibi, Shahnaz; Rowan, Andrew D.; Grainger, Angela; Mohanadas, Thivytra; Cant, Andrew J.; Slatter, Mary A.; Hambleton, Sophie; Lilic, Desa; Leahy, Timothy R.
- Abstract
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.
- Subjects
GAIN-of-function mutations; HEMATOPOIETIC stem cells; STEM cell transplantation; STEM cell treatment; OPPORTUNISTIC infections; AIDS-related opportunistic infections; RUXOLITINIB
- Publication
Journal of Clinical Immunology, 2019, Vol 39, Issue 8, p776
- ISSN
0271-9142
- Publication type
Article
- DOI
10.1007/s10875-019-00687-4