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

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State: Public
Version: Final published version
Serval ID
serval:BIB_7B8117A7C642
Type
Article: article from journal or magazin.
Publication sub-type
Case report (case report): feedback on an observation with a short commentary.
Collection
Publications
Institution
Title
Identification of an agrin mutation that causes congenital myasthenia and affects synapse function.
Journal
American Journal of Human Genetics
Author(s)
Huzé C., Bauché S., Richard P., Chevessier F., Goillot E., Gaudon K., Ben Ammar A., Chaboud A., Grosjean I., Lecuyer H.A., Bernard V., Rouche A., Alexandri N., Kuntzer T., Fardeau M., Fournier E., Brancaccio A., Rüegg M.A., Koenig J., Eymard B., Schaeffer L., Hantaï D.
ISSN
1537-6605[electronic]
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
85
Number
2
Pages
155-167
Language
english
Notes
Publication types: Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
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.
Keywords
Adult, Agrin/chemistry, Agrin/genetics, Animals, Biopsy, Cell Line, DNA Mutational Analysis, Dystroglycans/metabolism, Female, Humans, Male, Models, Chemical, Muscle Fibers, Skeletal/cytology, Muscle Fibers, Skeletal/metabolism, Muscle, Skeletal/metabolism, Muscle, Skeletal/pathology, Mutation, Missense, Myasthenic Syndromes, Congenital/genetics, Neuromuscular Junction/genetics, Neuromuscular Junction/metabolism, Pedigree, Protein Structure, Tertiary, Rats, Receptors, Cholinergic/genetics, Receptors, Cholinergic/metabolism, Recombinant Proteins/chemistry, Recombinant Proteins/metabolism, Synapses/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
08/10/2009 14:49
Last modification date
20/08/2019 14:37
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