Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2-S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder.
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Bohm J, Biancalana V, Dechene ET, Bitoun M, Pierson CR, Schaefer E, Karasoy H, Dempsey MA, Klein F, Dondaine N et al (2012) Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Hum Mutat 33(6):949–959
Kenniston JA, Lemmon MA (2010) Dynamin GTPase regulation is altered by PH domain mutations found in centronuclear myopathy patients. EMBO J 29:3054–3067
Liu YW, Lukiyanchuk V, Schmid SL (2011) Common membrane trafficking defects of disease-associated dynamin 2 mutations. Traffic 12:1620–1633
Achiriloaie M, Barylko B, Albanesi JP (1999) Essential role of the dynamin pleckstrin homology domain in receptor-mediated endocytosis. Mol Cell Biol 19:1410–1415
Gold ES, Underhill DM, Morrissette NS, Guo J, McNiven MA, Aderem A (1999) Dynamin 2 is required for phagocytosis in macrophages. The Journal of experimental medicine 190:1849–1856
Kruchten AE, McNiven MA (2006) Dynamin as a mover and pincher during cell migration and invasion. Journal of cell science 119:1683–1690
Nicholson G, Myers S (2006) Intermediate forms of Charcot–Marie–Tooth neuropathy: a review. Neuromolecular medicine 8:123–130
Orth JD, McNiven MA (2003) Dynamin at the actin-membrane interface. Curr Opin Cell Biol 15:31–39
Schafer DA (2004) Regulating actin dynamics at membranes: a focus on dynamin. Traffic 5:463–469
Thompson HM, Cao H, Chen J, Euteneuer U, McNiven MA (2004) Dynamin 2 binds gamma-tubulin and participates in centrosome cohesion. Nature cell biology 6:335–342
Elder GB, Dean D, McComas AJ, Paes B, DeSa D (1983) Infantile centronuclear myopathy. Evidence suggesting incomplete innervation. J Neurol Sci 60:79–88
Fidzianska A, Goebel HH (1994) Aberrant arrested in maturation neuromuscular junctions in centronuclear myopathy. J Neurol Sci 124:83–88
Sher JH, Rimalovski AB, Athanassiades TJ, Aronson SM (1967) Familial centronuclear myopathy: a clinical and pathological study. Neurology 17:727–742
Liewluck T, Shen XM, Milone M, Engel AG (2011) Endplate structure and parameters of neuromuscular transmission in sporadic centronuclear myopathy associated with myasthenia. Neuromuscul Disord 21:387–395
Robb SA, Sewry CA, Dowling JJ, Feng L, Cullup T, Lillis S, Abbs S, Lees MM, Laporte J, Manzur AY et al (2011) Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies. Neuromuscul Disord 21:379–386
Durieux AC, Vignaud A, Prudhon B, Viou MT, Beuvin M, Vassilopoulos S, Fraysse B, Ferry A, Laine J, Romero NB et al (2010) A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice. Hum Mol Genet 19:4820–4836
Durieux AC, Vassilopoulos S, Laine J, Fraysse B, Brinas L, Prudhon B, Castells J, Freyssenet D, Bonne G, Guicheney P et al (2012) A centronuclear myopathy—dynamin 2 mutation impairs autophagy in mice. Traffic 13:869–879
Cowling BS, Toussaint A, Amoasii L, Koebel P, Ferry A, Davignon L, Nishino I, Mandel JL, Laporte J (2011) Increased expression of wild-type or a centronuclear myopathy mutant of dynamin 2 in skeletal muscle of adult mice leads to structural defects and muscle weakness. Am J Pathol 178:2224–2235
Bitoun M, Maugenre S, Jeannet PY, Lacene E, Ferrer X, Laforet P, Martin JJ, Laporte J, Lochmuller H, Beggs AH et al (2005) Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet 37:1207–1209
Jeub M, Bitoun M, Guicheney P, Kappes-Horn K, Strach K, Druschky KF, Weis J, Fischer D (2008) Dynamin 2-related centronuclear myopathy: clinical, histological and genetic aspects of further patients and review of the literature. Clin Neuropathol 27:430–438
Bitoun M, Bevilacqua JA, Prudhon B, Maugenre S, Taratuto AL, Monges S, Lubieniecki F, Cances C, Uro-Coste E, Mayer M et al (2007) Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann Neurol 62:666–670
Dowling JJ, Low SE, Busta AS, Feldman EL (2010) Zebrafish MTMR14 is required for excitation-contraction coupling, developmental motor function and the regulation of autophagy. Hum Mol Genet 19:2668–2681
Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL (2009) Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genet 5:e1000372
Kwan KM, Fujimoto E, Grabher C, Mangum BD, Hardy ME, Campbell DS, Parant JM, Yost HJ, Kanki JP, Chien CB (2007) The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs. Dev Dyn 236:3088–3099
Westerfield M (1993) The zebrafish book. A guide for the laboratory use of zebrafish (Brachydanio rerio). Univ. of Oregon Press, Eugene
Dowling JJ, Gibbs E, Russell M, Goldman D, Minarcik J, Golden JA, Feldman EL (2008) Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res 102:423–431
Telfer WR, Busta AS, Bonnemann CG, Feldman EL, Dowling JJ (2010) Zebrafish models of collagen VI-related myopathies. Hum Mol Genet 19:2433–2444
Susman RD, Quijano-Roy S, Yang N, Webster R, Clarke NF, Dowling J, Kennerson M, Nicholson G, Biancalana V, Ilkovski B et al (2010) Expanding the clinical, pathological and MRI phenotype of DNM2-related centronuclear myopathy. Neuromuscul Disord 20:229–237
Harriman DG, Haleem MA (1972) Centronuclear myopathy in old age. J Pathol 108:237–247
Cartaud A, Stetzkowski-Marden F, Maoui A, Cartaud J (2011) Agrin triggers the clustering of raft-associated acetylcholine receptors through actin cytoskeleton reorganization. Biol Cell 103:287–301
Moransard M, Borges LS, Willmann R, Marangi PA, Brenner HR, Ferns MJ, Fuhrer C (2003) Agrin regulates rapsyn interaction with surface acetylcholine receptors, and this underlies cytoskeletal anchoring and clustering. J Biol Chem 278:7350–7359
Okamoto PM, Gamby C, Wells D, Fallon J, Vallee RB (2001) Dynamin isoform-specific interaction with the shank/ProSAP scaffolding proteins of the postsynaptic density and actin cytoskeleton. J Biol Chem 276:48458–48465
The authors wish to thank Angela Busta and Arden Trickey Glassman for technical help with the zebrafish experimentation. They also thank Dr. Jim Teener for assistance with the neurodiagnostic assessment of the patients. This work was supported by funds from the Program for Neurological Research and Discovery and the A. Alfred Taubman Medical Research Institute. EMG was supported by a Walbridge Aldinger Graduate Fellowship. This work was additionally supported by the National Institutes of Health [1K08AR054835 to JJD] and the Australian National Health and Medical Research Council [grants 1022707, 1031893 and 1035828 to NFC].
Conflict of interest
The authors declare no conflict of interest in connection with the submitted material.
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Gibbs, E.M., Clarke, N.F., Rose, K. et al. Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy. J Mol Med 91, 727–737 (2013) doi:10.1007/s00109-013-0994-4
- Neuromuscular junction
- Acetylcholinesterase inhibitor