Skip to main content
SpringerLink
Log in

The spectrum of congenital myasthenic syndromes

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The past decade saw remarkable advances in defining the molecular and genetic basis of the congenital myasthenic syndromes. These advances would not have been possible without antecedent clinical observations, electrophysiologic analysis, and careful morphologic studies that pointed to candidate genes or proteins. For example, a kinetic abnormality of the acetylcholine receptor (AChR) detected at the single channel level pointed to a kinetic mutation in an AChR subunit; endplate AChR deficiency suggested mutations residing in an AChR subunit or in rapsyn; absence of acetylcholinesterase (AChE) from the endplate predicted mutations in the catalytic or collagen-tailed subunit of this enzyme; and a history of abrupt episodes of apnea associated with a stimulation dependent decrease of endplate potentials and currents implicated proteins concerned with ACh resynthesis or vesicular filling. Discovery of mutations in endplate-specific proteins also prompted expression studies that afforded proof of pathogenicity, provided clues for rational therapy, lead to precise structure function correlations, and highlighted functionally significant residues or molecular domains that previous systematic mutagenesis studies had failed to detect. An overview of the spectrum of the congenital myasthenic syndromes suggests that most are caused by mutations in AChR subunits, and particularly in the ɛ subunit. Future studies will likely uncover new types of CMS that reside in molecules governing quantal release, organization of the synaptic basal lamina, and expression and aggregation of AChR on the postsynaptic junctional folds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Engel A. G, Ohno K., and Sine S. M. (1999) Congenital myasthenic syndromes, in Myasthenia Gravis and Myasthenic Disorders (Engel A. G., eds.) Oxford University Press, New York, pp. 251–297.

    Google Scholar 

  2. Ohno K., Tsujino A., Brengman J. M., Harper C. M., Bajzer Z., Udd B., Beyring R., Robb S., Kirkham F. J., and Engel A. G. (2001) Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc. Natl. Acad. Sci. USA 98, 2017–2022.

    Article  PubMed  CAS  Google Scholar 

  3. Walls T. J., Engel A. G., Nagel A. S., Harper C. M., and Trastek V. F. (1993) Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann NY Acad. Sci. 681, 461–468.

    Article  PubMed  CAS  Google Scholar 

  4. Bady B., Chauplannaz G., and Carrier H. (1987) Congenital Lambert-Eaton myasthenic syndrome. J. Neurol. Neurosurg. Psychiatry 50, 476–478.

    PubMed  CAS  Google Scholar 

  5. Maselli R. A., Kong D. Z., Bowe C. M., McDonald C. M., Ellis W. G., Agius M. A., Gomez C. M., Richman D. P., and Wollman R. L. (2001) Presynaptic congenital myasthenic syndrome due to quantal release deficiency. Neurology 57, 279–289.

    PubMed  CAS  Google Scholar 

  6. Mora M., Lambert E. H., and Engel A. G. (1987) Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 37, 206–214.

    PubMed  CAS  Google Scholar 

  7. Byring R. F., Pihko H., Shen X-M, et al. (2002) Congenital myasthenic syndrome associated with epsiodic apnea and sudden infant death. Neuromuscul. Disord. 12, 548–553.

    Article  PubMed  CAS  Google Scholar 

  8. Okuda T., Haga T., Kanai Y., Endou H., Ishihara T., and Katsura I. (2000) Identification and characterization of the high-affinity choline transporter. Nature Neurosci. 3, 120–125.

    Article  PubMed  CAS  Google Scholar 

  9. Apparasundaram S., Ferguson S. M., George A. L. Jr., and Blakely R. D. (2000) Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem. Biophys. Res. Commun. 276, 862–867.

    Article  CAS  Google Scholar 

  10. Oda Y., Nakanishi I., and Deguchi T. (1992) A complementary DNA for human choline acetyltransferase induces two forms of enzyme with different molecular weights in cultured cells. Brain Res. Mol. Brain Res. 16, 287–294.

    Article  PubMed  CAS  Google Scholar 

  11. Erickson J. D., Varoqui H., Eiden L. E., Schafer M. K., Modi W., Diebler M., Weihe E., Rand J., Bonner T. I., and Usdin T. B. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a ‘cholinergic’ gene locus. J. Biol. Chem. 269, 21,929–21,932.

    CAS  Google Scholar 

  12. Reimer R. J., Fon A. E., and Edwards R. H. (1998) Vesicular neurotransmitter transport and the presynaptic regulation of quantal size. Curr. Opin. Neurobiol. 8, 405–412.

    Article  PubMed  CAS  Google Scholar 

  13. Eiden L. E. (1998) The cholinergic gene locus. J. Neurochem. 70, 2227–2240.

    Article  PubMed  CAS  Google Scholar 

  14. Bööj S., Larsson P.-A., Dahllöf A.-G., and Dahlström A. (1986) Axonal transport of synapsin I and cholinergic synaptic vesicle-like material. Further immunohistochemical evidence for transport of axonal cholinergic transmitter vesicles in motor neurons. Acta. Physiol. Scand. 128, 155–165.

    PubMed  Google Scholar 

  15. Kiene L.-M., and Stadler H. (1987) Synaptic vesicles in electromotoneurones. I. Axonal transport, site of transmitter uptake and processing of a core proteoglycan during maturation. EMBO J. 6, 2209–2215.

    PubMed  CAS  Google Scholar 

  16. Llinás R., Sugimori M., Lin J.-W., Leopold P.-L., and Brady S. T. (1989) ATP-dependent directional movement of rat synaptic vesicles injected into the presynaptic terminal of squid giant synapse. Proc. Natl. Acad. Sci. USA. 86, 5656–5660.

    Article  PubMed  Google Scholar 

  17. Okada Y., Yamazaki H., Sekine-Aizawa Y., and Hirokawa N. (1995) The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81, 769–780.

    Article  PubMed  CAS  Google Scholar 

  18. Südhof T. C., and Jahn R. (1991) Proteins of synaptic vesicles involved in exocytosis and membrane recycling. Neuron 6, 665–677.

    Article  PubMed  Google Scholar 

  19. Engel A. G., Lambert E. H., and Gomez M. R. (1997) A new myasthenic syndrome with endplate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann. Neurol. 1, 315–330.

    Article  Google Scholar 

  20. Bon S., Coussen F., and Massoulié J. (1997) Quaternary associations of acetylcholinesterase. II. The polyproline attachment domain of the collagen tail. J. Biol. Chem. 272, 3016–3021.

    Article  PubMed  CAS  Google Scholar 

  21. Deprez P. N., and Inestrosa N. C. (1995) Two heparin-binding domains are present on the collagenic tail of asymmetric acetylcholinesterase. J. Biol. Chem. 270, 11,043–11,046.

    Article  CAS  Google Scholar 

  22. Ohno K., Engel A., G., Brengman J. M., Harper C. M., Shen X.-M., Heidenreich F. R., Vincent A., Milone M., Tan E., Demirci M., Walsh P., Nakano S., and Akiguchi I. (2000) The spectrum of mutations causing endplate acetylcholinesterase deficiency. Ann. Neurol. 47, 162–170.

    Article  PubMed  CAS  Google Scholar 

  23. Kimbell L. M., Ohno K., Rotundo R. L., and Engel A. G. (2001) Transplanting mutant human collagenic tailed acetylcholinesterase onto the frog neuromuscular junction: Evidence for an attachment defect in a congenital myasthenic syndrome. (Abstract) Mol. Biol. Cell 12(Suppl), 161a.

    Google Scholar 

  24. Prockop D. J., and Kivirikko K. I. (1995) Collagens: Molecular biology, diseases, and potentials for therapy. Annu. Rev. Biochem. 64, 403–434.

    Article  PubMed  CAS  Google Scholar 

  25. Ohno K., Brengman J. M., Tsujino A., and Engel A. G. (1998) Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proc. Natl. Acad. Sci. USA 95, 9654–9659.

    Article  PubMed  CAS  Google Scholar 

  26. Donger C., Krejci E., Serradell P., Eymard B., Bon S., Nicole S., Chateau D., Gary F., Fardeau M., Massoulié J., and Guicheney P. (1998) Mutation in the human acetylcholinesterase-associated gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency. Am. J. Hum. Genet. 63, 967–975.

    Article  PubMed  CAS  Google Scholar 

  27. Ohno K., Brengman J. M., Felice K. J., Cornblath D. R., and Engel A. G. (1999) Congenital endplate acetylcholinesterase deficiency caused by a nonsense mutation and an A-to-G splice site mutation at position +3 of the collagen-like tail subunit gene (COLQ): How does G at position +3 result in aberrant splicing? Am. J. Hum. Genet. 65, 635–644.

    Article  PubMed  CAS  Google Scholar 

  28. Shapira Y. A., Sadeh M. E., Bergtraum M. P., Tsujino A., Ohno K., Shen X.-M., Brengman J. M., Edwardson S., Matoh I., and Engel A. G. (2002) The novel COLQ mutations and variation of phenotypic expressivity due to G240X. Neurology 58, 603–609.

    PubMed  CAS  Google Scholar 

  29. Karlin A., and Akabas M. H. (1994) Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 15, 1231–1244.

    Article  Google Scholar 

  30. Prince R. J., and Sine S. M. (1998) The ligand binding domains of the nicotinic acetylcholine receptor, in The Nicotinic Acetylcholine Receptor: Current Views and Future Trends (Barrantes F. J., eds.) Landes Bioscience, Austin, TX, pp. 31–59.

    Google Scholar 

  31. Corringer J. P., Le Novère N., and Changeux J.-P. (2000) Nicotine receptors at the amino acid level. Annu. Rev. Pharmacol. Toxicol. 40, 431–458.

    Article  PubMed  CAS  Google Scholar 

  32. Galzi J.-L., Revah F., Black D., Goeldner M., Hirth C., and Changeux J.-P. (1990) Identification of a novel amino acid α-tyrosine 93 within the cholinergic ligand-binding sites of the acetylcholine receptor by photoaffinity labeling. J. Biol. Chem. 265, 10,430–10,437.

    CAS  Google Scholar 

  33. Czajkowski C., and Karlin A. (1995) Structure of the nicotinic receptor acetylcholine binding site. J. Biol. Chem. 270, 3160–3164.

    Article  PubMed  CAS  Google Scholar 

  34. Chiara D. C., Middleton R. E., and Cohen J. B. (1998) Identification of tryptophan 55 as the primary site of [3H]nicotine photoincorporation in the gamma subunit of Torpedo nicotinic acetylcholine receptor. FEBS Lett. 423, 223–226.

    Article  PubMed  CAS  Google Scholar 

  35. Wang D., Chirar D. C., Xie Y., and Cohen J. B. (2000) Probing the structure of the nicotinic acetylcholine receptor with 4-benzoylbenzoyl choline, a novel photoaffinity competitive antagonist. J. Biol. Chem. 275, 28,666–28,674.

    CAS  Google Scholar 

  36. Brejc K., van Dijk W. V., Schuurmans M., van der Oost J., Smit A. B., and Sixma T. K. (2001) Crystal structure of ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276.

    Article  PubMed  CAS  Google Scholar 

  37. Miyazawa A., Fujiyoshy Y., and Unwin N. (1999) Nicotinic acetylcholine receptor at 4.6Å resolution: Transverse tunnels in the channel wall. J. Mol. Biol. 288, 765–786.

    Article  PubMed  CAS  Google Scholar 

  38. Unwin N. (1995) Acetylcholine receptor channel imaged in the open state. Nature 373, 37–43.

    Article  PubMed  CAS  Google Scholar 

  39. Akabas M. H., Kaufmann C., Archdeacon P., and Karlin A. (1994) Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit. Neuron 13, 919–927.

    Article  PubMed  CAS  Google Scholar 

  40. Corringer J. P., Bertrand S., Galzi J.-L., Devillers-Thiéry A., Changeux J.-P., and Bertrand D. (1999) Mutational analysis of the charge selectivity filter of the α7 nicotinic acetylcholine receptor. Neuron 22, 831–843.

    Article  PubMed  CAS  Google Scholar 

  41. Milone M., Wang H.-L., Ohno K., Prince R. J., Shen X.-M., Brengman J. M., Griggs R. C., and Engel A. G. (1998) Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor ɛ subunit. Neuron 20, 575–588.

    Article  PubMed  CAS  Google Scholar 

  42. Ohno K., Hutchinson D. O., Milone M., Brengman J. M., Bouzat C., Sine S. M., and Engel A. G. (1995) Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the ɛ subunit. Proc. Natl. Acad. Sci. USA. 92, 758–762.

    Article  PubMed  CAS  Google Scholar 

  43. Sine S. M., Ohno K., Buzat C., Auerbach A., Milone M., Pruitt J. N., and Engel A. G. (1995) Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 15, 229–239.

    Article  PubMed  CAS  Google Scholar 

  44. Engel A. G., Ohno K., Milone M., Wang H.-L., Nakano S., Bouzat C., Pruitt J. N., Hutchinson D. O., Brengman J. M., Bren N., Sieb J. P., and Sine S. M. (1996) New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum. Mol. Genet. 5, 1217–1227.

    Article  PubMed  CAS  Google Scholar 

  45. Wang H.-L., Auerbach A., Bren N., Ohno K., Engel A. G., and Sine S. M. (1997) Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. J. Gen. Physiol. 109, 757–766.

    Article  PubMed  CAS  Google Scholar 

  46. Milone M., Wang H.-L., Ohno K., Fukudome T., Pruitt J. N., Bren N., Sine S. M., and Engel A. G. (1997) Slow-channel syndrome caused by enhanced activation, desensitization, and agonist binding affinity due to mutation in the M2 domain of the acetylcholine receptor alpha subunit. J. Neurosci. 17, 5651–5665.

    PubMed  CAS  Google Scholar 

  47. Gomez C. M., Maselli R., Gammack J., Lasalde J., Tamamizu s., Cornblath D. R., Lehar M., McNamee M., and Kuncl R. (1996) A beta-subunit mutation in the acetylcholine receptor gate causes severe slow-channel syndrome. Ann. Neurol. 39, 712–723.

    Article  PubMed  CAS  Google Scholar 

  48. Croxen R., Newland C., Beeson D., Oosterhuis H., Chauplanaz G., Vincent A., and Newsom-Davis J. (1997) Mutations in different functional domains of the human muscle acetylcholine receptor α subunit in patients with the slow-channel congenital myasthenic syndrome. Hum. Mol. Genet. 6, 767–774.

    Article  PubMed  CAS  Google Scholar 

  49. Ohno K., Milone M., Brengman J. M., Lo Monaco M., Evoli A., Tonali P., and Engel A. G. (1998) Slow-channel congenital myasthenic syndrome caused by a novel mutation in the acetylcholine receptor ɛ subunit. (Abstract) Neurology 50, A432.

    Google Scholar 

  50. Ohno K., Wang H.-L., Shen X.-M., Milone M., Bernasconi L., Sine S. M., and Engel A. G. (2000) Slow-channel mutations in the center of the M1 transmembrane domain of the acetylcholine receptor α subunit. (Abstract) Neurology 54(Suppl 3), A183.

    Google Scholar 

  51. Gomez C. M., Maselli R., Staub J., Day J. W., Cens T., Wollman R. L., and Charnet P. C. (1998) Novel δ and β subunit acetylcholine receptor mutations in the slow-channel syndrome demonstrate phenotypic variability. (Abstract) Soc. Neurosci. Abstr. 24, 484.

    Google Scholar 

  52. Grosman C., Salamone F. N., Sine S. M., and Auerbach A. (2000) The extracellular linker of muscle acetylcholine receptor channels is a gating control element. J. Gen. Physiol. 116, 327–339.

    Article  PubMed  CAS  Google Scholar 

  53. Monod J., Wyman J., and Changeux J.-P. (1965) On the nature of allosteric transitions: A plausible model. J. Mol. Biol. 12, 88–118.

    Article  PubMed  CAS  Google Scholar 

  54. Jackson M. B. (1989) Perfection of a synaptic receptor: kinetics and energetics of the acetylcholine receptor. Proc. Natl. Acad. Sci. USA 86, 2199–2203.

    Article  PubMed  CAS  Google Scholar 

  55. Labarca C., Nowak M. W., Zhang H., Tang L., Desphpande P., and Lester H. A. (1995) Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors. Nature 376, 514–516.

    Article  PubMed  CAS  Google Scholar 

  56. Dennis M., Giraudat J., Kotzyba-Hilbert F., Goeldner M., Hirth C., Chang J., Lazure C., and Cretien M. (1988) Amino acids of Torpedo marmotrata acetylcholine receptor alpha subunit labeled by a photoaffinity ligand for the acetylcholine binding site. Biochemistry. 27, 2346–2357.

    Article  PubMed  CAS  Google Scholar 

  57. Ohno K., Wang H.-L., Milone M., Bren N., Brengman J. M., Nakano S., Quiram P., Pruitt J. N., Sine S. M., and Engel A. G. (1996) Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ɛ subunit. Neuron 17, 157–170.

    Article  PubMed  CAS  Google Scholar 

  58. Shen X.-M., Ohno K., Milone M., Brengman, J. M., Spilsbury P. R., and Engel A. G. (2001) Fast-channel syndrome. (Abstract) Neurology 56(suppl. 3), A60.

  59. Shen X.-M., Tsujino A., Ohno K., Brengman J. M., Gingold M., and Engel A. G. (2000) A novel fast-channel congenital myasthenic syndrome caused by a mutation in the Cys-loop domain of the acetylcholine receptor ɛ subunit. (Abstract) Neurology 54(suppl 3), A138.

    Google Scholar 

  60. Wang H.-L., Milone M., Ohno K., Shen X.-M., Tsujino A., Batocchi A. P., Tonali P., Brengman J. M., Engel A. G., and Sine S. M. (1999) Acetylcholine receptor M3 domain: Stereochemical and volume contributions to channel gating. Nature Neurosci. 2, 226–233.

    Article  PubMed  CAS  Google Scholar 

  61. Wang H.-L., Ohno K., Milone M., Brengman J. M., Evoli A., Batocchi A. P., Middleton L., Christodoulou K., Engel A. G., and Sine S. M. (2000) Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. J. Gen. Physiol. 116, 449–460.

    Article  PubMed  CAS  Google Scholar 

  62. Shen X.-M., Ohno K., Fukudome T., Brengman J. M., and Engel A. G. (1999) Deletion of a single codon from the long cytoplasmic loop of the nAChR subunit gene causes brief single channel currents. (Abstract) Soc. Neurosci. Abstr. 25, 1721.

    Google Scholar 

  63. Brownlow S., Webster R., Croxen R., Brydson M., Neville B., Lin J.-P., Vincent A., Newsom-Davis J., and Beeson D. (2001) Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J. Clin. Invest. 108, 125–130.

    Article  PubMed  CAS  Google Scholar 

  64. Engel A. G., Ohno K., Bouzat C., Sine S. M., and Griggs R. G. (1996) End-plate acetylcholine receptor deficiency due to nonsense mutations in the ɛ subunit. Ann. Neurol. 40, 810–817.

    Article  PubMed  CAS  Google Scholar 

  65. Ohno K., Quiram P., Milone M., Wang H.-L., Harper C. M., Pruitt J. N., Brengman J. M., Pao L., Fischbeck K. H., Crawford T. O., Sine S. M., and Engel A. G. (1997) Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor ɛ subunit gene: identification and functional characterization of six new mutations. Hum. Mol. Genet. 6, 753–766.

    Article  PubMed  CAS  Google Scholar 

  66. Ohno K., Engel A. G., Milone M., Brengman J. M., Sieb J. P., and Iannaccone S. (1995) A congenital myasthenic syndrome with severe acetylcholine receptor deficiency caused by heteroallelic frameshifting mutations in the epsilon subunit. (Abstract) Neurology 45(Suppl 4), A283.

    Google Scholar 

  67. Ohno K., Anlar B., Özdirim E., Brengman J. M., De Bleecker J., and Engel A. G. (1998) Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann. Neurol. 44, 234–241.

    Article  PubMed  CAS  Google Scholar 

  68. Ohno K., Fukudome T., Nakano S., Milone M., Feasby T. E., Tyce G. M., and Engel A. G. (1996) Mutational analysis in a congenital myasthenic syndrome reveals a novel acetylcholine receptor epsilon subunit mutation. Soc. Neurosci. Abstr. 22, 234–234.

    Google Scholar 

  69. Middleton L., Ohno K., Christodoulou K., et al. (1999) Congenital myasthenic syndromes linked to chromosome 17p are caused by defects in acetylcholine receptor ɛ subunit gene. Neurology 53, 1076–1082.

    PubMed  CAS  Google Scholar 

  70. Croxen R., Beeson D., Vincent A., and Newsom-Davis J. (1996) Congenital myasthenic syndrome with a single nucleotide deletion at the intron/exon boundary in exon 12 of the gene encoding the acetylcholine receptor ɛ subunit. (Abstract) Ann. Neurol. 40, 513.

    Google Scholar 

  71. Croxen R., Newland C., Betty M., Vincent A., Newsom-Davis J., and Beeson D. (1999) Novel functional ɛ-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. Ann. Neurol. 46, 639–647.

    Article  PubMed  CAS  Google Scholar 

  72. Abicht A., Stucka R., Karcagi V., et al. (1999) A common mutation (ɛ1267delG) in congenital myasthenic patients of Gipsy ethnic origin. Neurology 53, 1564–1569.

    PubMed  CAS  Google Scholar 

  73. Ohno K., Anlar B., and Engel A. G. (1999) Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor ɛ subunit gene. Neuromuscul. Disord. 9, 131–135.

    Article  PubMed  CAS  Google Scholar 

  74. Nichols P., Croxen R., Vincent A., Rutter R., Hutchinson M., Newsom-Davis J., and Beeson D. (1999) Mutation of the acetylcholine receptor ɛ-subunit promoter in congenital myasthenic syndrome. Ann. Neurol. 45, 439–443.

    Article  PubMed  CAS  Google Scholar 

  75. Quiram P., Ohno K., Milone M., Patterson M. C., Pruitt N. J., Brengman J. M., Sine S. M., and Engel A. G. (1999) Mutation causing congenital myasthenia reveals acetylcholine receptor β/δ subunit interaction essential for assembly. J. Clin. Invest. 104, 1403–1410.

    PubMed  CAS  Google Scholar 

  76. Ohno K., and Engel A. G. (2002) Congenital myasthenic syndromes: gene mutations. Neuromuscul. Disord. (In press).

  77. Gautam M., Noakes P. G., Moscoso L., Rupp F., Scheller R. H., Merlie M. P., and Sanes J. R. (1996) Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 85, 525–535.

    Article  PubMed  CAS  Google Scholar 

  78. Burgess R. W., Nguyen Q. T., Son Y. J., Lichtman J. W., and Sanes J. R. (1999) Alternatively spliced isoforms of nerve- and muscle-derived agrin: Their roles at the neuromuscular junction. Neuron 23, 33–44.

    Article  PubMed  CAS  Google Scholar 

  79. Glass D. J., Bowen D. C., Stitt T. N., et al. (1996) Agrin acts via MuSK receptor complex. Cell 85, 513–523.

    Article  PubMed  CAS  Google Scholar 

  80. Apel E. D., Glass D. J., Moscosco L. M., Yancopoulos G. D., and Sanes J. R. (1997) Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Neuron 18, 623–625.

    Article  PubMed  CAS  Google Scholar 

  81. Smith C. L., Mittaud P., Prescott E. D., Fuhrer C., and Burden S. J. (2001) Src, Fyn, and Yes are not required for neuromuscular synapse formation but are necessary for stabilization of agrininduced clusters of acetylcholine receptors. J. Neurosci. 21, 3151–3160.

    PubMed  CAS  Google Scholar 

  82. Cartaud A., Coutant S., Petrucci T. C., and Cartaud J. (1998) Evidence for in situ and in vitro association between β-dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse. J. Biol. Chem. 273, 11,321–11,326.

    Article  CAS  Google Scholar 

  83. Tseng C. N., Yao Y., Wang J. M., Viroonchatapan N., Rothe E., and Wang Z. Z. (2001) A synaptic isoform of NRAP interacts with the postsynaptic 43K protein rapsyn and links it to the cytoskeleton at the neuromuscular junction. Soc. Neurosci. Abstr. 27, Program No. 694.6.

  84. Sandrock A. W., Dryer S. E., Rosen K. M., Gozani S. M., Kramer R., Theill L. E., and Fischbach G. D. (1997) Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science. 276, 599–603.

    Article  PubMed  Google Scholar 

  85. Si J., Luo Z., and Mei L. (1996) Induction of acetylcholine receptor gene expression by ARIA requires activation of mitogen-activated protein kinase. J. Biol. Chem. 271, 19,752–19,759.

    CAS  Google Scholar 

  86. Altiok N., Altiok K., and Changeux J.-P. (1997) Heregulin-stimulated acetylcholine receptor gene expression in muscle — requirement for MAP kinase and evidence for parallel inhibitory pathway independent electrical activity. EMBO J. 16, 717–725.

    Article  PubMed  CAS  Google Scholar 

  87. Belluardo N., Westerblad H., Mudo G., Casabona A., Bruton J., Caniglia G., Pastoris O., Grassi F., and Ibanez C. F. (2001) Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4. Moll. Cell. Neurosci. 18, 56–67.

    Article  CAS  Google Scholar 

  88. Gonzales M., Ruggiero F. P., Chang Q., Shi Y. J., Rich M. M., Kraner S., and Balice-Gordon R. J. (1999) Disruption of Trkb-mediated signaling induces disassembly of potsynaptic receptor clusters at neuromuscular junctions. Neuron 24, 567–583.

    Article  Google Scholar 

  89. Newey S. A., Gramolini A. O., Wu J., Izfeind G., Smin B. J., Vies K. E., and Ake D. J. (2001) A novel mechanism for modulating synaptic gene expression: Differential localization of α-dystrobrevin transcripts in skeletal muscle. Moll. Cell. Neurosci. 17, 127–140.

    Article  CAS  Google Scholar 

  90. Grady R. M., Merlie J. P., and Sanes J. R. (1997) Subtle neuromuscular defects in utrophin-deficient mice. J. Cell. Biol. 136, 871–882.

    Article  PubMed  CAS  Google Scholar 

  91. Adams M. E., Kramarcy M., Krall S. P., Rossi S. G., Rotundo R. L., Sealock R., and Froehner S. C. (2000) Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J. Cell Biol. 150, 1385–1398.

    Article  PubMed  CAS  Google Scholar 

  92. Banwell B. L., Russel J., Fukudome T., Shen X.-M., Stilling G., and Engel A. G. (1999) Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J. Neuropathol. Exp. Neurol. 58, 832–846.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, 55905, Rochester, MN

    Andrew G. Engel & Kinji Ohno

  2. Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Clinic, 55905, Rochester, MN

    Steven M. Sine

Authors
  1. Andrew G. Engel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kinji Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven M. Sine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew G. Engel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Engel, A.G., Ohno, K. & Sine, S.M. The spectrum of congenital myasthenic syndromes. Mol Neurobiol 26, 347–367 (2002). https://doi.org/10.1385/MN:26:2-3:347

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:26:2-3:347

Index Entries

Search

Navigation