Abstract
Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Arthritis / genetics*
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Arthritis / immunology
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Arthritis / pathology
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Arthritis / therapy
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Base Sequence
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Bone Marrow Transplantation
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Colitis / genetics*
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Colitis / immunology
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Colitis / pathology
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Colitis / therapy
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Dermatitis / genetics*
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Dermatitis / immunology
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Dermatitis / pathology
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Dermatitis / therapy
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Family
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Female
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Gene Expression
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Gene Knock-In Techniques
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Humans
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Infant
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Lymphoma, Large B-Cell, Diffuse / genetics*
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Lymphoma, Large B-Cell, Diffuse / immunology
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Lymphoma, Large B-Cell, Diffuse / pathology
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Lymphoma, Large B-Cell, Diffuse / therapy
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Mutation
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Pedigree
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Protein Kinase Inhibitors / pharmacology
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Syk Kinase / antagonists & inhibitors
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Syk Kinase / deficiency
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Syk Kinase / genetics*
Substances
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Protein Kinase Inhibitors
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SYK protein, human
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Syk Kinase