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: Frédéric Chevessier, Emmanuelle Girard, Jordi Molgó, Sönke Bartling, Jeanine Koenig, Daniel Hantaï, Veit Witzemann
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 17 Issue 22 Pg. 3577-95 (Nov 15 2008) ISSN: 1460-2083 [Electronic] England
• PMID: 18718936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cholinergic
• MUSK protein, human
• MuSK protein, mouse
• Receptor Protein-Tyrosine Kinases

Topics

• Animals
• Axons (physiology)
• Diaphragm (innervation, physiopathology)
• Disease Models, Animal
• Female
• Humans
• Kyphosis
• Locomotion
• Male
• Mice
• Microscopy, Electron
• Motor Endplate (physiopathology)
• Muscle Contraction
• Muscle Weakness
• Mutation, Missense
• Myasthenic Syndromes, Congenital (genetics, metabolism, physiopathology)
• Neuromuscular Junction (physiopathology, ultrastructure)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Receptors, Cholinergic (genetics, metabolism)
• Refractory Period, Electrophysiological
• Synaptic Transmission