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Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

Lin Wang1,2, Dominik Aschenbrenner3,4, Zhiyang Zeng5

  • 1Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.

Nature Genetics
|March 30, 2021
PubMed

Insights

Gain-of-function variants in Spleen tyrosine kinase (SYK) cause immune deficiency and inflammatory disease. These SYK variants are treatable with SYK inhibitors or bone marrow transplantation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Spleen tyrosine kinase (SYK) is a key regulator of immune cell signaling.
  • SYK is a validated therapeutic target for various immune-related disorders.

Purpose of the Study:

  • To investigate the role of damaging SYK variants in human immune deficiency and inflammatory diseases.
  • To characterize the functional consequences of identified SYK variants and evaluate therapeutic strategies.

Main Methods:

  • Identified monoallelic SYK variants in patients with immune deficiency and multi-organ inflammation.
  • Utilized a knock-in mouse model (SYK-Ser544Tyr) to study disease mechanisms.
  • Assessed the efficacy of a SYK inhibitor and bone marrow transplantation in the mouse model.

Main Results:

  • Six patients presented with immune deficiency, multi-organ inflammation (colitis, arthritis, dermatitis), and B cell lymphomas due to damaging SYK variants.
  • SYK variants demonstrated increased phosphorylation and enhanced downstream signaling, indicating a gain-of-function.
  • The SYK-Ser544Tyr mouse model recapitulated key features of the human disease.
  • Disease manifestations in the mouse model were partially ameliorated by SYK inhibition and wild-type bone marrow transplantation.

Conclusions:

  • Gain-of-function variants in SYK lead to a novel form of immune deficiency and inflammatory disease.
  • These SYK-driven inflammatory conditions represent a potentially treatable clinical entity.
  • Targeting SYK offers a therapeutic avenue for patients with these specific genetic variants.

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