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Charcot Marie Tooth Disease. A Single Disorder?
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Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C

John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy
Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
Leibniz-Institut für Analytische Wissenschaften -ISAS- e.V.; Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany
Department of Neuroscience, Karolinska Institutet, 171 65 Stockholm, Sweden
Department of Clinical Neuroscience, Karolinska Institutet, 171 65 Stockholm, Sweden
Department of Clinical Neurosciences, University of Cambridge, John Van Geest Cambridge Centre for Brain Repair, Forvie, Robinson way, Cambridge Biomedical Campus, Cambridge CB2 0PY, UK
Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Mathildenstrasse 1, 79106 Freiburg, Germany
Centro Nacional de Análisis Genómico, Center for Genomic Regulation, Barcelona Institute of Science and Technology, Baldri I reixac 4, 08028 Barcelona, Spain
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
Division of Neurology, Department of Medicine, The Ottawa Hospital, Riverside Drive, Ottawa, ON K1H 7X5, Canada
Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, Centre for Neuromuscular Disorders in Children, University Children’s Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(12), 4072;
Received: 24 October 2018 / Revised: 6 December 2018 / Accepted: 14 December 2018 / Published: 17 December 2018
(This article belongs to the Special Issue Research on Charcot-Marie-Tooth Disease, from Molecules to Therapy)
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The neuromuscular junction (NMJ) appears to be a site of pathology in a number of peripheral nerve diseases. Charcot-Marie-Tooth (CMT) 4C is an autosomal recessive, early onset, demyelinating neuropathy. Numerous mutations in the SH3TC2 gene have been shown to underlie the condition often associated with scoliosis, foot deformities, and reduced nerve conduction velocities. Mice with exon 1 of the Sh3tc2 gene knocked out demonstrate many of the features seen in patients. To determine if NMJ pathology is contributory to the pathomechanisms of CMT4C we examined NMJs in the gastrocnemius muscle of SH3TC2-deficient mice. In addition, we performed proteomic assessment of the sciatic nerve to identify protein factors contributing to the NMJ alterations and the survival of demyelinated axons. Morphological and gene expression analysis of NMJs revealed a lack of continuity between the pre- and post-synaptic apparatus, increases in post-synaptic fragmentation and dispersal, and an increase in expression of the gamma subunit of the acetylcholine receptor. There were no changes in axonal width or the number of axonal inputs to the NMJ. Proteome investigations of the sciatic nerve revealed altered expression of extracellular matrix proteins important for NMJ integrity. Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon. View Full-Text
Keywords: Charcot-Marie-Tooth disease 4C; SH3TC2; neuromuscular junction; mouse models; peripheral neuropathy; demyelination Charcot-Marie-Tooth disease 4C; SH3TC2; neuromuscular junction; mouse models; peripheral neuropathy; demyelination

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Cipriani, S.; Phan, V.; Médard, J.-J.; Horvath, R.; Lochmüller, H.; Chrast, R.; Roos, A.; Spendiff, S. Neuromuscular Junction Changes in a Mouse Model of Charcot-Marie-Tooth Disease Type 4C. Int. J. Mol. Sci. 2018, 19, 4072.

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