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Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib
- Source :
- Journal of clinical immunology. 39(8)
- Publication Year :
- 2019
-
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 :
- 0301 basic medicine
Male
Ruxolitinib
Primary Immunodeficiency Diseases
Immunology
SUMO protein
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Nitriles
medicine
Immunology and Allergy
Humans
Chronic mucocutaneous candidiasis
Child
Immunodeficiency
Janus kinase inhibitor
Janus Kinases
Mutation
biology
business.industry
Candidiasis, Chronic Mucocutaneous
Sumoylation
medicine.disease
030104 developmental biology
Pyrimidines
STAT1 Transcription Factor
Treatment Outcome
Gain of Function Mutation
Cancer research
biology.protein
Pyrazoles
Immunocompetence
business
030215 immunology
medicine.drug
Subjects
Details
- ISSN :
- 15732592
- Volume :
- 39
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of clinical immunology
- Accession number :
- edsair.doi.dedup.....d7816ab08296d16eb8df347ccdc993b5