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

  • Tariq Al Shehri
  • Kimberly Gilmour
  • Florian Gothe
  • Sam Loughlin
  • Shahnaz Bibi
  • Andrew D. Rowan
  • Angela Grainger
  • Thivytra Mohanadas
  • Andrew J. Cant
  • Mary A. Slatter
  • Sophie Hambleton
  • Desa Lilic
  • Timothy R. LeahyEmail author
Original Article


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.


STAT1 sumoylation combined immunodeficiency chronic mucocutaneous candidiasis 



The authors wish to acknowledge the good will of the patient and his parents for consenting to publication of this case report.

Author Contributions

TAS, ADR, DL: functional immunology laboratory experiments, manuscript preparation, and review.

SL, SB: NGS panel and Sanger sequencing of STAT1 gene, manuscript preparation, and review.

KG, AJC, MAS, TRL: manuscript preparation and review.

Funding Information

Authors DL and TAS were funded to undertake this research through a Medical Research Council Confidence in Concept Grant (Grant No. BH152850). Author TAS was funded by King Faisal Specialist Hospital & Research Centre grant, Saudi Arabia. Author FG was funded by Deutsche Forschungsgemeinschaft (GO2955/1-1 (F.G.)).

Compliance with Ethical Standards

Ethical approval was granted by the Great North Biobank (GNB), Reference No. 5458/10/H0906/22, and Newcastle Autoimmune Inflammatory Rheumatic Diseases (NAIRD) Research Biobank, Reference No. 10/H0106/30.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10875_2019_687_MOESM1_ESM.docx (421 kb)
ESM 1 (DOCX 420 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tariq Al Shehri
    • 1
    • 2
  • Kimberly Gilmour
    • 3
  • Florian Gothe
    • 1
  • Sam Loughlin
    • 4
  • Shahnaz Bibi
    • 4
  • Andrew D. Rowan
    • 1
  • Angela Grainger
    • 1
  • Thivytra Mohanadas
    • 1
  • Andrew J. Cant
    • 1
    • 5
  • Mary A. Slatter
    • 1
    • 5
  • Sophie Hambleton
    • 1
    • 5
  • Desa Lilic
    • 1
  • Timothy R. Leahy
    • 6
    Email author
  1. 1.Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK
  2. 2.Department of Pathology & Laboratory Medicine, Immunology LabKing Faisal Specialist Hospital & Research CentreRiyadhKingdom of Saudi Arabia
  3. 3.Department of Immunology, Camelia Botnar LaboratoriesGreat Ormond Street Hospital for ChildrenLondonUK
  4. 4.Regional Molecular Genetics LaboratoryGreat Ormond Street Hospital for ChildrenLondonUK
  5. 5.Department of Paediatric Immunology and BMTGreat North Children’s HospitalNewcastle upon TyneUK
  6. 6.Department of Paediatric Immunology and Infectious DiseasesChildren’s Health IrelandDublinIreland

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