Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 313 (5795): 1975-1978

Copyright © 2006 by the American Association for the Advancement of Science

Dok-7 Mutations Underlie a Neuromuscular Junction Synaptopathy

David Beeson,1* Osamu Higuchi,4 Jackie Palace,2 Judy Cossins,1 Hayley Spearman,1 Susan Maxwell,1 John Newsom-Davis,2 Georgina Burke,1 Peter Fawcett,3 Masakatsu Motomura,5 Juliane S. Müller,6 Hanns Lochmüller,6 Clarke Slater,3 Angela Vincent,1 Yuji Yamanashi4

Abstract: Congenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. One major subgroup of patients shows a characteristic "limb girdle" pattern of muscle weakness, in which the muscles have small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. We showed that recessive inheritance of mutations in Dok-7, which result in a defective structure of the neuromuscular junction, is a cause of CMS with proximal muscle weakness.

1 Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
2 Department of Clinical Neurology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.
3 School of Neurology, Neurobiology, and Psychiatry, University of Newcastle, NE2 4HH, UK.
4 Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113–8510, Japan.
5 First Department of Internal Medicine, Nagasaki University, Nagasaki 852–8501, Japan.
6 Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.

* To whom correspondence should be addressed. E-mail: dbeeson{at}

The Role of MuSK in Synapse Formation and Neuromuscular Disease.
S. J. Burden, N. Yumoto, and W. Zhang (2013)
Cold Spring Harb Perspect Biol 5, a009167
   Abstract »    Full Text »    PDF »
Somatic complex I disruptive mitochondrial DNA mutations are modifiers of tumorigenesis that correlate with low genomic instability in pituitary adenomas.
I. Kurelac, A. MacKay, M. B. K. Lambros, E. Di Cesare, G. Cenacchi, C. Ceccarelli, I. Morra, A. Melcarne, L. Morandi, F. M. Calabrese, et al. (2013)
Hum. Mol. Genet. 22, 226-238
   Abstract »    Full Text »    PDF »
The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome.
J. Cossins, W. W. Liu, K. Belaya, S. Maxwell, M. Oldridge, T. Lester, S. Robb, and D. Beeson (2012)
Hum. Mol. Genet. 21, 3765-3775
   Abstract »    Full Text »    PDF »
Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment.
Y. Yamanashi, T. Tezuka, and K. Yokoyama (2012)
J. Biochem. 151, 353-359
   Abstract »    Full Text »    PDF »
A valid mouse model of AGRIN-associated congenital myasthenic syndrome.
L. P. Bogdanik and R. W. Burgess (2011)
Hum. Mol. Genet. 20, 4617-4633
   Abstract »    Full Text »    PDF »
Fetal akinesia: review of the genetics of the neuromuscular causes.
G. Ravenscroft, E. Sollis, A. K. Charles, K. N. North, G. Baynam, and N. G. Laing (2011)
J. Med. Genet. 48, 793-801
   Abstract »    Full Text »    PDF »
Agrin Binds to the N-terminal Region of Lrp4 Protein and Stimulates Association between Lrp4 and the First Immunoglobulin-like Domain in Muscle-specific Kinase (MuSK).
W. Zhang, A.-S. Coldefy, S. R. Hubbard, and S. J. Burden (2011)
J. Biol. Chem. 286, 40624-40630
   Abstract »    Full Text »    PDF »
Testing the neuromuscular junction: what neurophysiology can offer the neurologist.
R. G. Whittaker (2011)
Practical Neurology 11, 303-307
   Full Text »    PDF »
Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing.
K. Gaudon, I. Penisson-Besnier, B. Chabrol, F. Bouhour, L. Demay, A. Ben Ammar, S. Bauche, C. Vial, G. Nicolas, B. Eymard, et al. (2010)
J. Med. Genet. 47, 795-796
   Abstract »    Full Text »    PDF »
Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L.
P. T. Hallock, C.-F. Xu, T.-J. Park, T. A. Neubert, T. Curran, and S. J. Burden (2010)
Genes & Dev. 24, 2451-2461
   Abstract »    Full Text »    PDF »
Myasthenia and related disorders of the neuromuscular junction.
J. Spillane, D. J. Beeson, and D. M. Kullmann (2010)
J. Neurol. Neurosurg. Psychiatry 81, 850-857
   Abstract »    Full Text »    PDF »
Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction.
R. A. Maselli, J. Arredondo, O. Cagney, J. J. Ng, J. A. Anderson, C. Williams, B. J. Gerke, B. Soliven, and R. L. Wollmann (2010)
Hum. Mol. Genet. 19, 2370-2379
   Abstract »    Full Text »    PDF »
Damage-Induced Neuronal Endopeptidase Is Critical for Presynaptic Formation of Neuromuscular Junctions.
K. Nagata, S. Kiryu-Seo, M. Maeda, K. Yoshida, T. Morita, and H. Kiyama (2010)
J. Neurosci. 30, 6954-6962
   Abstract »    Full Text »    PDF »
Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.
D. Lashley, J. Palace, S. Jayawant, S. Robb, and D. Beeson (2010)
Neurology 74, 1517-1523
   Abstract »    Full Text »    PDF »
Dok-7 promotes slow muscle integrity as well as neuromuscular junction formation in a zebrafish model of congenital myasthenic syndromes.
J. S. Muller, C. D. Jepson, S. H. Laval, K. Bushby, V. Straub, and H. Lochmuller (2010)
Hum. Mol. Genet. 19, 1726-1740
   Abstract »    Full Text »    PDF »
A treatable muscle disease.
G Burke, D Allen, R Arunachalam, D Beeson, and S Hammans (2009)
Practical Neurology 9, 233-236
   Full Text »    PDF »
Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients.
M. Milone, X. M. Shen, D. Selcen, K. Ohno, J. Brengman, S. T. Iannaccone, C. M. Harper, and A. G. Engel (2009)
Neurology 73, 228-235
   Abstract »    Full Text »    PDF »
Germline mutation in DOK7 associated with fetal akinesia deformation sequence.
J Vogt, N V Morgan, T Marton, S Maxwell, B J Harrison, D Beeson, and E R Maher (2009)
J. Med. Genet. 46, 338-340
   Abstract »    Full Text »    PDF »
Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome.
R A Maselli, J J Ng, J A Anderson, O Cagney, J Arredondo, C Williams, H B Wessel, H Abdel-Hamid, and R L Wollmann (2009)
J. Med. Genet. 46, 203-208
   Abstract »    Full Text »    PDF »
Dok-7 Activates the Muscle Receptor Kinase MuSK and Shapes Synapse Formation.
A. Inoue, K. Setoguchi, Y. Matsubara, K. Okada, N. Sato, Y. Iwakura, O. Higuchi, and Y. Yamanashi (2009)
Science Signaling 2, ra7
   Abstract »    Full Text »    PDF »
Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions.
F. A. Court, T. H. Gillingwater, S. Melrose, D. L. Sherman, K. N. Greenshields, A. J. Morton, J. B. Harris, H. J. Willison, and R. R. Ribchester (2008)
J. Cell Sci. 121, 3901-3911
   Abstract »    Full Text »    PDF »
A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions.
F. Chevessier, E. Girard, J. Molgo, S. Bartling, J. Koenig, D. Hantai, and V. Witzemann (2008)
Hum. Mol. Genet. 17, 3577-3595
   Abstract »    Full Text »    PDF »
IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis.
M. I. Leite, S. Jacob, S. Viegas, J. Cossins, L. Clover, B. P. Morgan, D. Beeson, N. Willcox, and A. Vincent (2008)
Brain 131, 1940-1952
   Abstract »    Full Text »    PDF »
Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes.
V. Mihaylova, J. S. Muller, J. J. Vilchez, M. A. Salih, M. M. Kabiraj, A. D'Amico, E. Bertini, J. Wolfle, F. Schreiner, G. Kurlemann, et al. (2008)
Brain 131, 747-759
   Abstract »    Full Text »    PDF »
Mutations Causing DOK7 Congenital Myasthenia Ablate Functional Motifs in Dok-7.
J. Hamuro, O. Higuchi, K. Okada, M. Ueno, S.-i. Iemura, T. Natsume, H. Spearman, D. Beeson, and Y. Yamanashi (2008)
J. Biol. Chem. 283, 5518-5524
   Abstract »    Full Text »    PDF »
Synaptic differentiation is defective in mice lacking acetylcholine receptor {beta}-subunit tyrosine phosphorylation.
M. B. Friese, C. S. Blagden, and S. J. Burden (2007)
Development 134, 4167-4176
   Abstract »    Full Text »    PDF »
Gene Mutations in Congenital Myasthenic Syndromes.
J. G. Millichap (2007)
AAP Grand Rounds 18, 33
   Full Text »    PDF »
Gene Mutations in Congenital Myasthenic Syndromes.
J. G. Milichap (2007)
AAP Grand Rounds 18, 21-22
   Full Text »    PDF »
Analysis of a Shc Family Adaptor Protein, ShcD/Shc4, That Associates with Muscle-Specific Kinase.
N. Jones, W. R. Hardy, M. B. Friese, C. Jorgensen, M. J. Smith, N. M. Woody, S. J. Burden, and T. Pawson (2007)
Mol. Cell. Biol. 27, 4759-4773
   Abstract »    Full Text »    PDF »
Dok-3 plays a nonredundant role in negative regulation of B-cell activation.
C.-H. Ng, S. Xu, and K.-P. Lam (2007)
Blood 110, 259-266
   Abstract »    Full Text »    PDF »
Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes.
J. S. Muller, A. Herczegfalvi, J. J. Vilchez, J. Colomer, L. L. Bachinski, V. Mihaylova, M. Santos, U. Schara, M. Deschauer, M. Shevell, et al. (2007)
Brain 130, 1497-1506
   Abstract »    Full Text »    PDF »
Clinical features of the DOK7 neuromuscular junction synaptopathy.
J. Palace, D. Lashley, J. Newsom-Davis, J. Cossins, S. Maxwell, R. Kennett, S. Jayawant, Y. Yamanashi, and D. Beeson (2007)
Brain 130, 1507-1515
   Abstract »    Full Text »    PDF »
Dok-1 and Dok-2 are negative regulators of T cell receptor signaling.
T. Yasuda, K. Bundo, A. Hino, K. Honda, A. Inoue, M. Shirakata, M. Osawa, T. Tamura, H. Nariuchi, H. Oda, et al. (2007)
Int. Immunol. 19, 487-495
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882