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Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3229-3240; doi:10.1093/hmg/ddh333
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved

MUSK, a new target for mutations causing congenital myasthenic syndrome

Frédéric Chevessier1, Brice Faraut1, Aymeric Ravel-Chapuis2, Pascale Richard1,3, Karen Gaudon1,3, Stéphanie Bauché1, Cassandra Prioleau1, Ruth Herbst6, Evelyne Goillot2, Christine Ioos1, Jean-Philippe Azulay7, Shahram Attarian7, Jean-Paul Leroy1,8, Emmanuel Fournier4, Claire Legay9, Laurent Schaeffer2, Jeanine Koenig1,10, Michel Fardeau1, Bruno Eymard1,5, Jean Pouget7 and Daniel Hantaï1,*

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

Received September 16, 2004; Accepted October 12, 2004

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.

* To whom correspondence should be addressed at: INSERM U582, Institut de Myologie, Hôpital de la Salpêtrière, 47, Boulevard de l'Hôpital, 75651 Paris, Cedex 13, France. Tel: +33 142165706; Fax: +33 142165700; Email: d.hantai{at}myologie.chups.jussieu.fr


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