Identification of an agrin mutation that causes congenital myasthenia and affects synapse function

Huze, C. and Bauche, S. and Richard, P. and Chevessier, F. and Goillot, E. and Gaudon, K. and Ben Ammar, A. and Chaboud, A. and Grosjean, I. and Lecuyer, H. -A. and Bernard, V. and Rouche, A. and Alexandri, N. and Kuntzer, T. and Fardeau, M. and Fournier, E. and Brancaccio, A. and Ruegg, M. A. and Koenig, J. and Eymard, B. and Schaeffer, L. and Hantai, D.. (2009) Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. American Journal of Human Genetics, 85 (2). pp. 155-167.

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We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G<C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to alpha-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Univ. of Chicago Press
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:12 Apr 2019 15:48
Deposited On:22 Mar 2012 13:28

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