Titre :
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Generation of a mouse model for Schwartz-Jampel syndrome : role of perlecan in neuromuscular junction formation and/or maintenance (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Stum M ;
Girard E ;
Davoine CS ;
Molgo J ;
Tabti N ;
Willer JC ;
Fontaine B ;
Krejci E ;
Nicole S
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 125
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Langues:
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Anglais
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Mots-clés :
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acétylcholinestérase
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colloque
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électrodiagnostic
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électromyographie
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jonction neuromusculaire
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mutation génétique
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perlecan
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souris modèle
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syndrome de Schwartz-Jampel de type I
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Résumé :
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Communication n° 640. Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive human disease. Patients suffer from functional handicap with myotonia and chondrodystrophy that appear during chidlhood. We previously demonstrated that SJS was due to mutations in the perlecan gene. This result reveals a new physiopathological mechanism leading to human myotonia since perlecan is not a voltage-gated ion channel but a secreted proteoglycan present in basal laminae. To understand this mechanism, we have developed a SJS mouse model. We had to reproduce in mouse the hypomorph effect of SJS mutations. As we observed that SJS homozygous truncating mutations were gathered in the C-terminus of perlecan, we chose to mimic this effect. We used a mouse ES cell line, developed by a gene-trap approach, with insertion of the gene-trap vector into the 3'end of the perlecan gene deleting the C-terminus of perlecan. A mouse line was established and was explored to determine whether it reproduced the SJS phenotype. Heterozygous mice were normal. Homozygous mutants developed chondrodystrophy and locomotor defects mimicking myotonia with various degrees of severity. Immunostaining on fibroblasts and skeletal muscles from mutants revealed reduced level of perlecan mimicking the perlecan deficiency observed in SJS patients. EMG analyses revealed lower amplitude of evoked action potentials at 1 month of age, not related to muscle degeneration as checked on skeletal muscle sections. Electrophysiological recordings of synaptic transmission revealed higher frequency of giant miniature end plate potentials. Morphological analyses showed major modifications of neuromuscular junctions (NMJ) with lack of pretzel-like shape and acethylcholinesterase deficiency. These preliminary data strongly suggest a role of perlecan in NMJ formation and/or maintenance. Works are in progress to further characterize this SJS mouse model and understand the role of perlecan in muscle physiology.
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