The muscle-specific kinase (MuSK)-IgG1-3 antibodies that are seen in patients with myasthenia gravis (MG) who are MuSK positive are pathogenic, found a new study published in the journal Neurology Neuroimmunology & Neuroinflammation. However, they seem to act through a noncanonical pathway. 

To explore the mechanism of action of MuSK-IgG1-3 antibodies, a team of researchers exposed mouse myotubes to MuSK-IgG13 or MuSK-IgG4 antibodies with or without purified agrin, which plays a crucial role in the development of the neuromuscular junction during embryogenesis. 

Read more about the pathophysiology of MG

The researchers then immunoprecipitated MuSK, downstream of kinase 7 (DOK7), and βAChR and checked their phosphorylation levels. Finally, they measured agrin and agrin-independent acetylcholine receptor (AChR) clusters.

The results showed that IgG1-3 MuSK antibodies reduced the clustering of AChR but did not inhibit the phosphorylation of MuSK induced by agrin. 

Moreover, the well-established pathway initiated by MuSK, which results in the phosphorylation of βAChR via DOK7 remained intact following MuSK-IgG1-3 exposure and was agrin-independent. However, the AChR clusters did not form, and the number of AChR micro-clusters that form before full clusters and that of myotubes surface AChRs were reduced. 

The researchers also conducted transcriptomic analysis but this did not clarify, which pathways may be involved in the process. However, they reported that the SHP2 inhibitor, NSC-87877, increased the number of micro clusters and fully formed AChR clusters.

“Further studies should throw light on the mechanisms involved at the neuromuscular junction,” the authors concluded.

MG is a rare disease affecting the neuromuscular junction. Most cases are characterized by the presence of antibodies against the AChR. However, some patients also have autoantibodies against MuSK.


Cao M, Liu WW, Maxwell S, et al. IgG1-3 MuSK antibodies inhibit AChR cluster formation, restored by SHP2 inhibitor, despite normal MuSK, DOK7, or AChR subunit phosphorylation. Neurol Neuroimmunol Neuroinflamm. Published online August 15, 2023. doi:10.1212/NXI.0000000000200147