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

Nature Medicine volume 7, pages 365–368 (2001)Cite this article

Abstract

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present1. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness2. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab)3 have not been elucidated, but there is evidence that they also have an antibody-mediated disorder4,5, with the antibodies directed towards another, previously unidentified muscle-surface–membrane target6,7,8. Here we show that 70% of AChR-Ab–seronegative MG patients, but not AChR-Ab–seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction9,10,11,12. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab–seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

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Figure 1: Antibodies from AChR-Ab–seronegative MG patients bind to MuSK.
Figure 2: MuSK antibodies can be detected by ELISA.
Figure 3: MuSK IgG antibodies induce AChR clusters but inhibit agrin-induced clustering.

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Acknowledgements

We thank U. Schwarz for his support; C. Hopf for participating in cloning some of the constructs; A. Evoli and S. Robb for two of the plasmas and clinical information; and C.-M. Becker, C. Schuster and D. Roberts for critical reading of the manuscript. JMcC is supported by a Wellcome Trust Research Training Fellowship. J.N.-D. and A.V. thank the Muscular Dystrophy Campaign/Myasthenia Gravis Association for support.

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Authors and Affiliations

  1. Max Planck Institute for Developmental Biology, Tübingen, Germany

    Werner Hoch & Sigrun Helms

  2. Neurosciences Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK

    John McConville, John Newsom-Davis & Angela Vincent

  3. Department of Neurology, University of Tübingen, Tübingen, Germany

    Arthur Melms

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  1. Werner Hoch
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Correspondence to Werner Hoch or Angela Vincent.

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Hoch, W., McConville, J., Helms, S. et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7, 365–368 (2001). https://doi.org/10.1038/85520

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