Muscle-specific tyrosine-protein kinase (MuSK)

Muscle-specific tyrosine-protein kinase (MuSK) is a transmembrane receptor tyrosine kinase that plays a fundamental role in the development and maintenance of the neuromuscular junction (NMJ) [1, 2]. It is primarily expressed in skeletal muscle and serves as the central organizer of the postsynaptic membrane [4, 12]. MuSK is activated by the nerve-derived proteoglycan agrin, which binds to the LRP4 co-receptor, triggering MuSK autophosphorylation and a downstream signaling cascade involving Dok-7 and rapsyn [6, 12]. This process is essential for the clustering of acetylcholine receptors (AChRs) at the synapse, ensuring robust neuromuscular transmission [3, 7]. Dysfunction of MuSK, either through genetic mutations or autoimmune attack by IgG4 autoantibodies, leads to severe neuromuscular disorders such as congenital myasthenic syndrome and MuSK-positive myasthenia gravis [3, 6, 11]. Patients with MuSK-positive myasthenia gravis often present with severe bulbar and respiratory symptoms and may respond poorly to standard acetylcholinesterase inhibitors [6, 14]. Therapeutic interventions focus on stabilizing the NMJ through MuSK agonists or reducing the burden of pathogenic autoantibodies using B-cell depleting agents and FcRn inhibitors [9, 10, 14]. Emerging treatments like MuSK-specific CAAR-T cells and agonist monoclonal antibodies represent novel approaches to directly modulate MuSK signaling or its associated immune response [11, 13].

Other names

Muscle-specific kinaseMuscle-specific tyrosine protein kinase receptorMuscle, skeletal receptor tyrosine-protein kinaseMUSK

Agonism, B-cell depletion, FcRn inhibition, Acetylcholinesterase inhibition, Potassium channel blockade