Mutations in the SYK gene are responsible for a newly described phenotype with severe immunodeficiency, multi-organ inflammatory disease involving the intestines, liver, skin, joints and central nervous system, and a predisposition to B cell lymphoma. This is the result of an international study published in Nature Genetics. The researchers of the study found in six patients monoallelic missense mutations as the genetic cause of their condition. Subsequently, they further investigated one of the identified variants in a mouse model to elucidate its functional effects.

Spleen tyrosine kinase, the protein encoded by the SYK gene, is an important molecule in immune signaling. Among other functions, SYK is needed for the proper development of B cells, which are responsible for the production of antibodies. In their study, the researchers explored one of the identified SYK variants and discovered that it caused a gain of protein function and led to constitutive activation of the signaling pathway and immune dysregulation. Interestingly, SYK-inhibiting molecules are already being used in the treatment of other disorders. The new insights into the function of SYK gained in this study might therefore aid in the development of new options to treat patients with immune dysregulation.