Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the ne uromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present(1). These an tibodies cause loss of AChR numbers and function, and lead to failure of ne uromuscular transmission with muscle weakness(2). The pathogenic mechanisms acting in the 20% of patients with generalized MC who are seronegative for AChR-antibodies (AChR-Ab)(3) have not been elucidated, but there is eviden ce that they also have an antibody-mediated disorder(4,5), with the antibod ies directed towards another, previously unidentified muscle-surface-membra ne target(6-8). Here we show that 70% of AChR-Ab-seronegative MC patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies agains t the muscle-specific receptor tyrosine kinase, MUSK. MuSK mediates the agr in-induced clustering of AChRs during synapse formation, and is also expres sed at the mature neuromuscular junction(9-12). The MUSK antibodies were sp ecific for the extracellular domains of MUSK expressed in transfected COS7 cells and strongly inhibited MUSK function in cultured myotubes. Our result s indicate the involvement of MUSK antibodies in the pathogenesis of AChR-A b-seronegative MC, thus defining two immunologically distinct forms of the disease. Measurement of MUSK antibodies will substantially aid diagnosis an d clinical management.