title: A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions.
abstract: 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 (musk(V789M/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 (musk(V789M/-) mice). We report here that musk(V789M/V789M) mice present no obvious abnormal phenotype regarding weight, muscle function and viability. In contrast, adult musk(V789M/-) mice suffer from severe muscle weakness, exhibit shrinkage of pelvic and scapular regions and hunchback. Musk(V789M/-) 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 musk(V789M/-) 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 musk(V789M/-) 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.
authors: Max-Planck-Institut für Medizinische Forschung, Heidelberg, Germany. frederic.chevessier@mpimf-heidelberg.mpg.de
authors: Frédéric
authors: F
authors: Chevessier
authors: Emmanuelle
authors: E
authors: Girard
authors: Jordi
authors: J
authors: Molgó
authors: Sönke
authors: S
authors: Bartling
authors: Jeanine
authors: J
authors: Koenig
authors: Daniel
authors: D
authors: Hantaï
authors: Veit
authors: V
authors: Witzemann
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D003964:Diaphragm / Q000294:innervation* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007738:Kyphosis; D008124:Locomotion; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009045:Motor Endplate / Q000503:physiopathology; D009119:Muscle Contraction; D018908:Muscle Weakness; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000503:physiopathology* / Q000648:ultrastructure; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D009435:Synaptic Transmission
chemical_list: D011950:Receptors, Cholinergic; C095714:MUSK protein, human; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases