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

Tariq Al Shehri1,2, Kimberly Gilmour3, Florian Gothe1

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

Journal of Clinical Immunology
|September 13, 2019
PubMed

Insights

A novel STAT1 mutation impairs sumoylation, causing gain-of-function immune deficiency. Janus kinase inhibitor treatment partially reversed STAT1 hyperactivity but did not restore full immune function.

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 1 (STAT1) mutations can cause gain-of-function, leading to immune dysregulation such as chronic mucocutaneous candidiasis (CMC) and combined immunodeficiency (CID).
  • STAT1 function is regulated by post-translational modifications, including sumoylation, which affects its stability and transcriptional activity.

Observation:

  • A 10-year-old boy presented with CMC/CID due to a novel mutation in the STAT1 small ubiquitin molecule (SUMO) consensus site.
  • This mutation impaired STAT1 sumoylation, resulting in delayed dephosphorylation and constitutive activation (gain-of-function).

Findings:

  • Treatment with a Janus kinase inhibitor (jakinib) partially reversed STAT1 hyper-phosphorylation and downstream transcriptional activity.
  • However, jakinib therapy did not restore Interleukin-17 (IL-17) and Interleukin-22 (IL-22) production, and the patient remained susceptible to opportunistic infections.

Implications:

  • STAT1 gain-of-function mutations affecting sumoylation can be partially reversed by JAK inhibitors.
  • JAK inhibitor therapy may serve as a bridge to definitive treatments like hematopoietic stem cell transplantation for these immunodeficiencies, rather than a standalone long-term solution.
Keywords:
STAT1chronic mucocutaneous candidiasiscombined immunodeficiencysumoylation

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