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  A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions

Chevessier, F., Girard, E., Molgó, J., Bartling, S., Koenig, J., Hantaï, D., et al. (2008). A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions. Human Molecular Genetics, 17(22), 3577-3595. doi:10.1093/hmg/ddn251.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-014A-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-DBCD-3
Genre: Journal Article

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 Creators:
Chevessier, Frédéric1, 2, Author              
Girard, Emmanuelle, Author
Molgó, Jordi, Author
Bartling, Sönke, Author
Koenig, Jeanine, Author
Hantaï, Daniel, Author
Witzemann, Veit1, 2, Author              
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              

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 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.

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Language(s): eng - English
 Dates: 2008-07-132008-08-162008-08-212008-11-15
 Publication Status: Published in print
 Pages: 19
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 Rev. Type: Peer
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 17 (22) Sequence Number: - Start / End Page: 3577 - 3595 Identifier: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153