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Human Molecular Genetics Advance Access published online on October 20, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh333
© 2004 by Oxford University Press
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Article

MUSK, a new target for mutations causing congenital myasthenic syndrome

Frédéric Chevessier 1, Brice Faraut 1, Aymeric Ravel-Chapuis 2, Pascale Richard 3, Karen Gaudon 3, Stéphanie Bauché 1, Cassandra Prioleau 1, Ruth Herbst 4, Evelyne Goillot 2, Christine Ioos 1, Jean-Philippe Azulay 5, Shahram Attarian 5, Jean-Paul Leroy 6, Emmanuel Fournier 7, Claire Legay 8, Laurent Schaeffer 2, Jeanine Koenig 9, Michel Fardeau 1, Bruno Eymard 10, Jean Pouget 5, and Daniel Hantaï 11*

1 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France
2 CNRS/ENS UMR 5161 & IFR128, École Normale Supérieure, Lyon, France
3 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France; Unité Fonctionnelle de Cardiogénétique et Myogénétique, Service de Biochimie B & IFR "Coeur, Muscle, Vaisseaux", Hôpital de la Salpêtrière, Paris, France
4 Brain Research Institute, Medical University Vienna, Vienna, Austria
5 Service de Neurologie et Maladies Neuromusculaires, Hôpital Universitaire La Timone & IFR CNRS "Sciences du Cerveau et de la Cognition", Marseilles, France
6 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France; CHU Morvan, Brest, France
7 Service d'Electrophysiologie & IFR "Neurosciences", Hôpital de la Salpêtrière, Paris, France
8 CNRS UMR 8544, École Normale Supérieure, Paris, France
9 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France; Université Bordeaux II, Bordeaux, France
10 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, Paris, France; Fédération de Neurologie Mazarin & IFR "Neurosciences", Hôpital de la Salpêtrière, Paris, France
11 INSERM U582 & IFR "Coeur, Muscle, Vaisseaux", Institut de Myologie, Hôpital de la Salpêtrière and Université Pierre et Marie Curie, 47, Boulevard de l'Hôpital, 75651 Paris Cedex 13, France

* To whom correspondence should be addressed.
Daniel Hantaï, E-mail: d.hantai{at}myologie.chups.jussieu.fr


  Abstract

We report the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in acetylcholine receptor (AChR) {varepsilon}-subunit and MuSK expression.

In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The frameshift mutation led to the absence of MuSK expression. The missense mutation did not affect MuSK catalytic kinase activity but diminished expression and stability of MuSK leading to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of the missense mutation induced, within a week, a phenotype similar to the patient muscle biopsy: a severe decrease in synaptic AChR and an aberrant axonal outgrowth.

These results strongly suggest that the missense mutation, in the presence of a null mutation on the other allele, is responsible for the dramatic synaptic changes observed in the patient.


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