Myasthenia gravis (MG) is a disease of neuromuscular transmission with clinical features of weakness and fatigue which is mainly caused by antibodies to nicotinic acetylcholine receptor (AChR) in skeletal muscle. However, the sera from some patients with generalized MG (10-20 %) lack anti-AChR antibodies and they are termed “seronegative myasthenia gravis”; the disease is nevertheless caused by humoral factors as suggested by that the neuromuscular transmission block is transferable to mice by their serum samples. The search for non-AChR pathogenic antigens has recently been focused on muscle-specific tyrosine kinase (MuSK) and ryanodine receptor (RyR). The MuSK is a key protein necessary for the signal transduction from agrin (nerve-derived signal) to rapsyn (cross-linker of AChR) to form AChR cluster and primary scaffold in the postsynaptic membrane. Anti-MuSK antibodies are found in 40-70 % of seronegative MG patients with clinical features distinct from those of seropositive (anti-AChR-positive) MG patients. The RyR is a protein essential for the excitation-contraction coupling in skeletal muscle where it functions as a calcium release channel in the sarcoplasmic reticulum. The anti-RyR antibodies, mainly reactive with the C-terminal regions in the molecular structure, are detected in not only seropositive but also seronegative MG patients, suggesting a research direction to search for pathogenic antigens other than AChR and MuSK.
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