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Congenital myasthenic syndromes: Genetic defects of the neuromuscular junction

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Abstract

Congenital myasthenic syndromes (CMS) stem from defects in presynaptic, synaptic, and postsynaptic proteins. The presynaptic CMS are associated with defects that curtail the evoked release of acetylcholine (ACh) quanta or the resynthesis of ACh. Insufficient resynthesis of ACh is now known to be caused by mutations that reduce the expression, catalytic efficiency, or both of choline acetyltransferase. The synaptic CMS are caused by mutations in the collagenic tail subunit (ColQ) of the endplate species of acetylcholinesterase that prevent ColQ from associating with catalytic subunits or from insertion into the synaptic basal lamina. With one exception, postsynaptic CMS identified to date are associated with a kinetic abnormality or decreased expression of the acetylcholine receptor (AChR). Numerous mutations have now been identified in subunits of AChR that alter the kinetics or surface expression of the receptor. The kinetic mutations increase or decrease the synaptic response to ACh and result in slow- and fast-channel syndromes, respectively. Most mutations that reduce surface expression of AChR reside in the receptor’s εsubunit and are partially compensated by residual expression of the fetal-type γ subunit. Null mutations in both alleles of other AChR subunits are likely lethal, owing to absence of a substituting subunit.

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References and Recommended Reading

  1. Walls TJ, Engel AG, Nagel AS, Harper CM, Trastek VF: Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann N Y Acad Sci 1993, 681:461–468.

    Article  PubMed  CAS  Google Scholar 

  2. Mora M, Lambert EH, Engel AG: Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 1987, 37:206–214.

    PubMed  CAS  Google Scholar 

  3. Engel AG, Lambert EH, Gomez MR: A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann Neurol 1977, 1:315–330.

    Article  PubMed  CAS  Google Scholar 

  4. Engel AG, Lambert EH, Mulder DM, et al.: A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982, 11:553–569.

    Article  PubMed  CAS  Google Scholar 

  5. Engel AG, Hutchinson DO, Nakano S, et al.: Myasthenic syndromes attributed to mutations affecting the epsilon subunit of the acetylcholine receptor. Ann N Y Acad Sci 1993, 681:496–508.

    Article  PubMed  CAS  Google Scholar 

  6. Vincent A, Newsom-Davis J, Wray D, et al.: Clinical and experimental observations in patients with congenital myasthenic syndromes. Ann N Y Acad Sci 1993, 681:451–460.

    Article  PubMed  CAS  Google Scholar 

  7. McQuillen MP: Familial limb-girdle myasthenia. Brain 1966, 89:121–132.

    Article  PubMed  CAS  Google Scholar 

  8. Sadeh M: Benign congenital myasthenic syndrome with facial malformations. Acta Myologica 2000, 19:33–36.

    Google Scholar 

  9. Bady B, Chauplannaz G, Carrier H: Congenital Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1987, 50:476–478.

    Article  PubMed  CAS  Google Scholar 

  10. Maselli RA, Kong DZ, Bowe CM, et al.: Presynaptic congenital myasthenic syndrome due to quantal release deficiency. Neurology 2001, 57:279–289.

    PubMed  CAS  Google Scholar 

  11. Ohno K, Tsujino A, Brengman JM, et al.: Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci USA 2001, 98:2017–2022. Describes the genomic structure of human choline acetyltransferase and reports 10 recessive mutations that reduce the expression or catalytic efficiency of the enzyme in a presynaptic congenital myasthenic syndrome.

    Article  PubMed  CAS  Google Scholar 

  12. Engel AG, Ohno K, Sine SM: Congenital myasthenic syndromes. Myasthenia Gravis and Myasthenic Disorders. Edited by Engel AG. New York:Oxford University Press; 1999:251–297.

    Google Scholar 

  13. Okuda T, Haga T, Kanai Y, et al.: Identification and characterization of the high-affinity choline transporter. Nature Neurosci 2000, 3:120–125.

    Article  PubMed  CAS  Google Scholar 

  14. Apparsundaram S, Ferguson SM, George AL Jr, Blakely RD: Molecular cloning of a human, hemicholinium-3-sensitive choline transporter. Biochem Biophys Res Commun 2000, 276:862–867.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Erickson JD, Varoqui H, Eiden LE, et al.: Functional identification of a vesicular acetylcholine transporter and its expression from a ‘cholinergic’ gene locus. J Biol Chem 1994, 269:21929–21932.

    PubMed  CAS  Google Scholar 

  17. Reimer RJ, Fon AE, Edwards RH: Vesicular neurotransmitter transport and the presynaptic regulation of quantal size. Curr Opin Neurobiol 1998, 8:405–412.

    Article  PubMed  CAS  Google Scholar 

  18. Eiden LE: The cholinergic gene locus. J Neurochem 1998, 70:2227–2240.

    Article  PubMed  CAS  Google Scholar 

  19. Ohno K, Engel AG, Brengman JM, et al.: The spectrum of mutations causing endplate acetylcholinesterase deficiency. Ann Neurol 2000, 47:162–170. Reports nine COLQ mutations and classifies COLQ mutations into four classes.

    Article  PubMed  CAS  Google Scholar 

  20. Donger C, Krejci E, Serradell P, et al.: Mutation in the human acetylcholinesterase-associated gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency. Am J Hum Genet 1998, 63:967–975.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  22. Deprez PN, Inestrosa NC: Two heparin-binding domains are present on the collagenic tail of asymmetric acetylcholinesterase. J Biol Chem 1995, 270:11043–11046.

    Article  PubMed  CAS  Google Scholar 

  23. Prockop DJ, Kivirikko KI: Collagens: molecular biology, diseases, and potentials for therapy. Ann Rev Biochem 1995, 64:403–434.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Ohno K, Brengman JM, Felice KJ, Cornblath DR, Engel AG: 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 1999, 65:635–644.

    Article  PubMed  CAS  Google Scholar 

  26. Brengman JM, Shapira YA, Sadeh M, et al.: Neomutations in the collagenic tail subunit (ColQ) of acetylcholinesterase [abstract]. Neurology 2001, 56(suppl 3):60–61.

    Google Scholar 

  27. Banwell BL, Russel J, Fukudome T, et al.: Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol 1999, 58:832–846.

    PubMed  CAS  Google Scholar 

  28. Dougherty DA, Lester HA: Snails, synapses and smokers. Nature 2001, 411:252–253.

    Article  PubMed  CAS  Google Scholar 

  29. Brejc K, van Dijk WV, Schuurmans M, et al.: Crystal structure of ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 2001, 411:269–276. Relevant to interpretation of the effects of mutations in the extracellular part of AChR.

    Article  PubMed  CAS  Google Scholar 

  30. Fukudome T, Ohno K, Brengman JM, Engel AG: Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor. Neuroreport 1998, 9:1907–1911.

    Article  PubMed  CAS  Google Scholar 

  31. Harper CM, Engel AG: Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998, 43:480–484.

    Article  PubMed  CAS  Google Scholar 

  32. Ohno K, Wang HL, Milone M, et al.: Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. Neuron 1996, 17:157–170.

    Article  PubMed  CAS  Google Scholar 

  33. Harper CM, Engel AG: Treatment of 31 congenital myasthenic syndrome patients with 3,4-diaminopyridine [abstract]. Neurology 2000, 54(suppl 3):A395.

    Google Scholar 

  34. Ohno K, Hutchinson DO, Milone M, et al.: Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the ε subunit. Proc Natl Acad Sci USA 1995, 92:758–762.

    Article  PubMed  CAS  Google Scholar 

  35. Sine SM, Ohno K, Bouzat C, et al.: Mutation of the acetylcholine receptor a subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 1995, 15:229–239.

    Article  PubMed  CAS  Google Scholar 

  36. Engel AG, Ohno K, Milone M, et al.: New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1996, 5:1217–1227.

    Article  PubMed  CAS  Google Scholar 

  37. Wang HL, Auerbach A, Bren N, et al.: Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. J Gen Physiol 1997, 109:757–766.

    Article  PubMed  CAS  Google Scholar 

  38. Milone M, Wang HL, Ohno K, et al.: 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 1997, 17:5651–5665.

    PubMed  CAS  Google Scholar 

  39. Gomez CM, Maselli R, Gammack J, et al.: A beta-subunit mutation in the acetylcholine receptor gate causes severe slow-channel syndrome. Ann Neurol 1996, 39:712–723.

    Article  PubMed  CAS  Google Scholar 

  40. Croxen R, Newland C, Beeson D, et al.: Mutations in different functional domains of the human muscle acetylcholine receptor a subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1997, 6:767–774.

    Article  PubMed  CAS  Google Scholar 

  41. Ohno K, Milone M, Brengman JM, et al.: Slow-channel congenital myasthenic syndrome caused by a novel mutation in the acetylcholine receptor ε subunit [abstract]. Neurology 1998, 50:A432.

    Google Scholar 

  42. Ohno K, Wang HL, Shen XM, et al.: Slow-channel mutations in the center of the M1 transmembrane domain of the acetylcholine receptor α subunit [abstract]. Neurology 2000, 54(suppl 3):A183.

    Google Scholar 

  43. Gomez CM, Maselli R, Staub J: Novel δ and β subunit acetylcholine receptor mutations in the slow-channel syndrome demonstrate phenotypic variability [abstract]. Soc Neurosci Abstr 1998, 24:484.

    Google Scholar 

  44. Grosman C, Salamone FN, Sine SM, Auerbach A: The extracellular linker of muscle acetylcholine receptor channels is a gating control element. J Gen Physiol 2000, 116:327–339.

    Article  PubMed  CAS  Google Scholar 

  45. Shen XM, Ohno K, Milone M, et al.: Fast-channel syndrome [abstract]. Neurology 2001, 56(suppl 3):A60.

    Google Scholar 

  46. Shen XM, Tsujino A, Ohno K, et al.: A novel fast-channel congenital myasthenic syndrome caused by a mutation in the Cys-loop domain of the acetylcholine receptor ε subunit. Neurology 2000, 54(Suppl 3):A138.

    Google Scholar 

  47. Wang HL, Milone M, Ohno K, et al.: Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. Nature Neurosci 1999, 2:226–233.

    Article  PubMed  CAS  Google Scholar 

  48. Milone M, Wang HL, Ohno K, et al.: Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor ε subunit. Neuron 1998, 20:575–588.

    Article  PubMed  CAS  Google Scholar 

  49. Wang HL, Ohno K, Milone M, et al.: Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. J Gen Physiol 2000, 116:449–460.

    Article  PubMed  CAS  Google Scholar 

  50. Shen XM, Ohno K, Fukudome T, Brengman JM, Engel AG: Deletion of a single codon from the long cytoplasmic loop of the nAChR subunit gene causes brief single channel currents [abstract]. Soc Neurosci Abstr 1999, 25:1721.

    Google Scholar 

  51. Beeson DM, Brownlow S, Webster R: Arthrogryposis multiplex congenita and fast channel congenital myasthenic syndrome in a child with heteroallelic AChR δ subunit mutations. J Clin Invest 2001, 108:125–130. First description of arthrogryposis caused by a genetic defect in an AChR subunit gene.

    Article  PubMed  Google Scholar 

  52. Gautam M, Noakes PG, Moscoso L, et al.: Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell 1996, 85:525–535.

    Article  PubMed  CAS  Google Scholar 

  53. Mittaud P, Marangi A, Erb-Vögtli S, Uhrer C: Agrin induced activation of acetylcholine receptor-bound Src family kinases requires rapsyn an correlates with acetylcholine receptor clustering. J Biol Chem 2001, 276:14505–14513.

    PubMed  CAS  Google Scholar 

  54. Glass DJ, Bowen DC, Stitt TN, et al.: Agrin acts via MuSK receptor complex. Cell 1996, 85:513–523.

    Article  PubMed  CAS  Google Scholar 

  55. Gautam M, Noakes PG, Mudd J, et al.: Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 1995, 377:232–236.

    Article  PubMed  CAS  Google Scholar 

  56. Apel ED, Glass DJ, Moscosco LM, Yancopoulos GD, Sanes JR: Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Neuron 1997, 18:623–625.

    Article  PubMed  CAS  Google Scholar 

  57. Ramarao MK, Cohen JB: Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn. Proc Natl Acad Sci USA 1998, 95:4007–4012.

    Article  PubMed  CAS  Google Scholar 

  58. Sandrock AW, Dryer SE, Rosen KM, et al.: Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 1997, 276:599–603.

    Article  PubMed  Google Scholar 

  59. Si J, Luo Z, Mei L: Induction of acetylcholine receptor gene expression by ARIA requires activation of mitogen-activated protein kinase. J Biol Chem 1996, 271:19752–19759.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  61. Newey SA, Gramolini AO, Wu J, et al.: A novel mechanism for modulating synaptic gene expression: Differential localization of α-dystrobrevin transcripts in skeletal muscle. Mol Cell Neurosci 2001, 17:127–140.

    Article  PubMed  CAS  Google Scholar 

  62. Grady RM, Merlie JP, Sanes JR: Subtle neuromuscular defects in utrophin-deficient mice. J Cell Biol 1997, 136:871–882.

    Article  PubMed  CAS  Google Scholar 

  63. Adams ME, Kramarcy M, Krall SP, et al.: Absence of α-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J Cell Biol 2000, 150:1385–1398.

    Article  PubMed  CAS  Google Scholar 

  64. Milone M, Shen XM, Ohno K, et al.: Unusual congenital myasthenic syndrome with endplate AChR deficiency caused by alpha subunit mutations and a remitting-relapsing course [abstract]. Neurology 1999, 52(suppl 2):185–186.

    Google Scholar 

  65. Quiram P, Ohno K, Milone M, et al.: Mutation causing congenital myasthenia reveals acetylcholine receptor β/α subunit interaction essential for assembly. J Clin Invest 1999, 104:1403–1410.

    Article  PubMed  CAS  Google Scholar 

  66. Ohno K, Shen XM, Fukudome T, et al.: First report of acetylcholine receptor δ subunit mutation causing endplate AChR deficiency [abstract]. Neurology 2001, 56(suppl 3):232–233.

    Google Scholar 

  67. Nichols P, Croxen R, Vincent A, et al.: Mutation of the acetylcholine receptor ε-subunit promoter in congenital myasthenic syndrome. Ann Neurol 1999, 45:439–443.

    Article  PubMed  CAS  Google Scholar 

  68. Ohno K, Anlar B, Engel AG: Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor ε subunit gene. Neuromuscul Disord 1999, 9:131–135.

    Article  PubMed  CAS  Google Scholar 

  69. Abicht A, Stucka R, Song IH, et al.: Genetic analysis of the entire AChR ε-subunit gene in 52 congenital myasthenic families. Acta Myologica 2000, 19:23–27.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  71. Ohno K, Anlar B, özdirim E, et al.: Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol 1998, 44:234–241.

    Article  PubMed  CAS  Google Scholar 

  72. Ohno K, Quiram P, Milone M, et al.: Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor ε subunit gene: identification and functional characterization of six new mutations. Hum Mol Genet 1997, 6:753–766.

    Article  PubMed  CAS  Google Scholar 

  73. Sieb JP, Kraner S, Rauch M, Steinlein OK: Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations. Hum Genet 2000, 107:160–464.

    Article  PubMed  CAS  Google Scholar 

  74. Deymeer F, Serdaroglu P, Gülsen-Parman Y, öztürk A, özdemir C: Clinical characteristics of a group of Turkish patients having a benign CMS phenotype with ptosis and marked ophthalmoparesis and mutations in the acetylcholine rceptor epsilon subunit gene. Acta Myologica 2000, 19:29–32.

    Google Scholar 

  75. Brengman JM, Ohno K, Milone M, et al.: Identification and functional characterization of eight novel acetylcholine receptor mutations in six congenital myasthenic syndrome kinships [abstract]. Neurology 2000, 54(suppl 3):A182-A183.

    Google Scholar 

  76. Ohno K, Engel AG, Milone M, et al.: A congenital myasthenic syndrome with severe acetylcholine receptor deficiency caused by heteroallelic frameshifting mutations in the epsilon subunit [abstract]. Neurology 1995, 45(suppl 4):A283.

    Google Scholar 

  77. Milone M, Ohno K, Pruitt JN, et al.: Congenital myasthenic syndrome due to frameshifting acetylcholine receptor epsilon subunit mutation. Soc Neurosci Abstr 1996, 22:1942–1942.

    Google Scholar 

  78. Croxen R, Young C, Slater C, et al.: Endplate g- and e subunit mRNA levels in AChR deficiency syndrome due to ε subunit null mutations. Brain 2001, 124:1362–1372. Demonstrates presence of normal levels of e subunit mRNA at the endplate with frameshifting mutations in the ε subunit that reduce the surface expression of AChR.

    Article  PubMed  CAS  Google Scholar 

  79. Ohno K, Fukudome T, Nakano S, et al.: Mutational analysis in a congenital myasthenic syndrome reveals a novel acetylcholine receptor epsilon subunit mutation. Soc Neurosci Abstr 1996, 22:234–234.

    Google Scholar 

  80. Brengman JM, Ohno K, Shen XM, Engel AG: Congenital myasthenic syndrome due to two novel mutations in the acetylcholine receptor ε subunit gene [abstract]. Muscle Nerve 1998, 21(suppl 7):S120.

    Google Scholar 

  81. Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RG: End-plate acetylcholine receptor deficiency due to nonsense mutations in the ε subunit. Ann Neurol 1996, 40:810–817.

    Article  PubMed  CAS  Google Scholar 

  82. Croxen R, Newland C, Betty M, et al.: Novel functional e-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. Ann Neurol 1999, 46:639–647.

    Article  PubMed  CAS  Google Scholar 

  83. Abicht A, Stucka R, Karcagi V, et al.: A common mutation (ε1267delG) in congenital myasthenic patients of Gipsy ethnic origin. Neurology 1999, 53:1564–1569. Demonstrates a founder effect for the å1267delG mutation.

    PubMed  CAS  Google Scholar 

  84. Sieb JP, Kraner S, Schrank B, et al.: Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation. Ann Neurol 2000, 48:379–383.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA

    Kinji Ohno MD, PhD & Andrew G. Engel MD

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Ohno, K., Engel, A.G. Congenital myasthenic syndromes: Genetic defects of the neuromuscular junction. Curr Neurol Neurosci Rep 2, 78–88 (2002). https://doi.org/10.1007/s11910-002-0057-7

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