MAST3, the microtubule-associated serine-threonine kinase 3, is involved in multiple biological functions. It plays a role in regulating the immune response, as seen in its association with Inflammatory Bowel Disease (IBD) by modulating the TLR4 signaling pathway and NF-κB activity [3]. It also impacts cytoskeleton organization, intracellular signal transduction, and peptidyl-serine phosphorylation [2]. In the brain, it may be important for normal neurodevelopment.

In individuals with epilepsy, de novo missense variants in the STK domain of MAST3 were identified. These variants may confer a gain-of-function, as in vitro analysis showed increased phosphorylation of the target ARPP-16 in HEK293T cells transfected with mutant MAST3 cDNA. MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally [1]. In rheumatoid arthritis, MAST3 is up-regulated in synovial tissue and fibroblast-like synoviocytes (FLSs) of affected rats. Its overexpression promotes FLS proliferation and inflammatory response, potentially via the NF-κB signaling pathway [2].

In summary, MAST3 is a crucial gene involved in immune regulation, neurodevelopment, and inflammatory processes. Its role in epilepsy and rheumatoid arthritis, as revealed through in vitro and human-based studies, highlights its significance in understanding these disease mechanisms. The discovery of MAST3-associated variants in patients provides insights into potential pathogenic mechanisms, which may guide future research and treatment strategies for these diseases.