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          Institute: MPI für medizinische Forschung     Collection: Arbeitsgruppe Witzemann / Koenen     Display Documents

ID: 420265.0, MPI für medizinische Forschung / Arbeitsgruppe Witzemann / Koenen
A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions
Translation of Title:A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions
Authors:Chevessier, Frédéric; Girard, E.; Molgó, J.; Bartling, S.; Koenig, J.; Hantai, D.; Witzemann, Veit
Date of Publication (YYYY-MM-DD):2008-11-15
Title of Journal:Hum. Mol. Gen.
Journal Abbrev.:Hum. Mol. Gen.
Issue / Number:22
Start Page:3577
End Page:3595
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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.
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:wkaiser
Affiliations:MPI f�r medizinische Forschung/Arbeitsgruppe Witzemann / Koenen
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