Human Molecular Genetics Advance Access originally published online on August 21, 2008
Human Molecular Genetics 2008 17(22):3577-3595; doi:10.1093/hmg/ddn251
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A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions
1 Max-Planck-Institut für Medizinische Forschung, Jahnstrasse 29, 69120 Heidelberg, Germany 2 Inserm, U686, Biologie des Jonctions Neuromusculaires Normales et Pathologiques, 75005 Paris, France 3 CNRS, Institut de Neurobiologie Alfred Fessard-FRC2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire—UPR 9040, 91118 Gif sur Yvette, France 4 Abteilung Medizinische Physik in der Radiologie, Deutsches Krebsforschungzentrum, 69120 Heidelberg, Germany 5 Université Bordeaux II, 33076, Bordeaux, France 6 Inserm, U582, Institut de Myologie, Hôpital de la Salpêtrière, 75013 Paris, France 7 AP-HP, Centre de référence des maladies neuromusculaires Paris-Est, Hôpital de la Salpêtrière, Paris, France
* To whom correspondence should be addressed. Tel: +49 6221486475; Fax: +49 6221486459; Email: frederic.chevessier{at}mpimf-heidelberg.mpg.de
Received July 13, 2008; Accepted August 16, 2008
In the muscle-specific tyrosine kinase receptor gene MUSK, a heteroallelic missense and a null mutation were identified in a patient suffering from a congenital myasthenic syndrome (CMS). We generated one mouse line carrying the homozygous missense mutation V789M in musk (muskV789M/V789M mice) and a second hemizygous line, resembling the patient genotype, with the V789M mutation on one allele and an allele lacking the kinase domain (muskV789M/– mice). We report here that muskV789M/V789M mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult muskV789M/– mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. MuskV789M/– diaphragm develops less force upon direct or nerve-induced stimulation. A profound tetanic fade is observed following nerve-evoked muscle contraction, and fatigue resistance is severely impaired upon a train of tetanic nerve stimulations. Electrophysiological measurements indicate that fatigable muscle weakness is due to impaired neurotransmission as observed in a patient suffering from a CMS. The diaphragm of adult muskV789M/– mice exhibits pronounced changes in endplate architecture, distribution and innervation pattern. Thus, the missense mutation V789M in MuSK acts as a hypomorphic mutation and leads to insufficiency in MuSK function in muskV789M/– mutants. These mutant mice represent valuable models for elucidating the roles of MuSK for synapse formation, maturation and maintenance as well as for studying the pathophysiology of a CMS due to MuSK mutations.