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

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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.

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Acknowledgments

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

Funding

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.)).

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Author notes

  1. Tariq Al Shehri

    Present address: Department of Pathology & Laboratory Medicine, Immunology Lab, King Faisal Specialist Hospital & Research Centre, Riyadh, Kingdom of Saudi Arabia

  2. Desa Lilic and Timothy R. Leahy contributed equally to this work.

Authors and Affiliations

  1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

    Tariq Al Shehri, Florian Gothe, Andrew D. Rowan, Angela Grainger, Thivytra Mohanadas, Andrew J. Cant, Mary A. Slatter, Sophie Hambleton & Desa Lilic

  2. Department of Immunology, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children, London, UK

    Kimberly Gilmour

  3. Regional Molecular Genetics Laboratory, Great Ormond Street Hospital for Children, London, UK

    Sam Loughlin & Shahnaz Bibi

  4. Department of Paediatric Immunology and BMT, Great North Children’s Hospital, Newcastle upon Tyne, UK

    Andrew J. Cant, Mary A. Slatter & Sophie Hambleton

  5. Department of Paediatric Immunology and Infectious Diseases, Children’s Health Ireland, Crumlin, Dublin, D12 N512, Ireland

    Timothy R. Leahy

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  1. Tariq Al Shehri
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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.

Corresponding author

Correspondence to Timothy R. Leahy.

Ethics declarations

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.

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The authors declare that they have no conflict of interest.

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Al Shehri, T., Gilmour, K., Gothe, F. et al. Novel Gain-of-Function Mutation in Stat1 Sumoylation Site Leads to CMC/CID Phenotype Responsive to Ruxolitinib. J Clin Immunol 39, 776–785 (2019). https://doi.org/10.1007/s10875-019-00687-4

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

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