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.