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

Huzé, C., Bauché, S., Richard, P., Chevessier, F., Goillot, E., Gaudon, K., et al. (2009). Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. The American Journal of Human Genetics, 85(2), 155-167. doi:10.1016/j.ajhg.2009.06.015.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-1147-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-115E-B
Genre: Journal Article
Alternative Title : Identification of an agrin mutation that causes congenital myasthenia and affects synapse function

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 Creators:
Huzé, Carolin, Author
Bauché, Stephanie, Author
Richard, Pascale, Author
Chevessier, Frédéric1, 2, Author              
Goillot, Evelyne, Author
Gaudon, Karen, Author
Ammar, Asma Ben, Author
Chaboud, Anne, Author
Grosjean, Isabelle, Author
Lecuyer, Heba-Aude, Author
Bernard, Véronique, Author
Rouche, Andrée, Author
Alexandri, Nektaria, Author
Kuntzer, Thierry, Author
Fardeau, Michel, Author
Fournier, Emmanuel, Author
Brancaccio, Andrea, Author
Rüegg, Markus A., Author
Koenig, Janine, Author
Eymard, Bruno, Author
Schaeffer, Laurent, AuthorHantaï, Daniel, Author more..
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2009-06-232009-03-262009-06-232009-07-232009-08-14
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 664636
DOI: 10.1016/j.ajhg.2009.06.015
URI: http://www.ncbi.nlm.nih.gov/pubmed/19631309
Other: 7538
 Degree: -

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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 85 (2) Sequence Number: - Start / End Page: 155 - 167 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1