Molecular Genetics of Congenital Myasthenic Syndromes

Abstract

Congenital myasthenic syndromes (CMS) are heterogeneous disorders caused by congenital defects of molecules expressed at the neuromuscular junctions. Clinical features include fatigable muscle weakness, amyotrophy and minor facial anomalies. Mutations have been identified in 18 genes encoding acetylcholine receptor (AChR) subunits (CHRNA1, CHRNB1, CHRND and CHRNE); skeletal muscle sodium channel (SCN4A); signalling molecules driving AChR clustering and subserving maintenance and differentiation of the postsynaptic region (AGRN, LRP4, MUSK and DOK7); postsynaptic structural proteins (RAPSN and PLEC); synaptic β2 laminin, which promotes presynaptic differentiation, and synaptic collagen Q; presynaptic choline acetyltransferase and enzymes in subserving protein glycosylation (GFPT1, DPAGT1, ALG14, and ALG2). The CMS are caused by recessive mutations except for the slow‐channel CMS. The recent development of the exome sequencing has speeded identification of causative mutations. Mutations in glycosylation genes were recently discovered, but the mechanisms by which they impair neuromuscular signal transmission have not been fully elucidated.

Key Concepts:

  • Congenital myasthenic syndromes are caused by germline mutations in molecules expressed at the neuromuscular junction (NMJ).

  • Muscle nicotinic acetylcholine receptor (AChR) is a pentameric ligand‐gated ion channel in the stoichiometry of α2βδϵ subunits.

  • Missense mutations in AChR subunit genes can cause abnormally long and brief ion channel openings resulting in slow‐ and fast‐channel myasthenic syndromes, respectively.

  • Primary endplate AChR deficiency can be due to low‐expressor or null mutations in the AChR ϵ subunit. The phenotype in case of biallelic low‐expressor or null mutations in the ϵ subunit is rescued by expression of the foetal γ subunit. Biallelic null mutations in non‐ϵ are embryonic lethal mutations.

  • A second group of endplate AChR deficiency is caused by mutations in signalling molecules including agrin, LRP4, MuSK, Dok‐7, which drive AChR clustering.

  • The third group of endplate AChR deficiency stems from mutations in the postsynaptic structural proteins of rapsyn or plectin.

  • Mutations in enzymes subserving the N‐glycosylation pathway of GFPT1, DPAGT1, ALG14 and ALG2 cause limb‐girdle CMS with tubular aggregates.

  • Endplate acetylcholinesterase (AChE) deficiency is caused by mutations in collagen Q (ColQ), which anchors AChE to the synaptic basal lamina.

  • Protein‐anchoring therapy, in which ectopically expressed AChE/ColQ complex is specifically anchored to the neuromuscular junction using the proprietary binding motifs, markedly ameliorates myasthenic symptoms of Colq‐knockout mice.

  • Mutations in choline acetyltransferase (ChAT) cause defective resynthesis of ACh at the nerve terminal and a CMS associated with frequent episodic apnoea.

Keywords: congenital myasthenic syndromes; neuromuscular junction; muscle nicotinic acetylcholine receptor; skeletal muscle sodium channel; acetylcholinesterase; choline acetyltransferase; protein glycosylation

Figure 1.

Mutations causing CMS have been identified in 18 genes (red letters). AChR is composed of α, β, δ and ϵ subunits encoded by four different genes.

Figure 2.

CMS mutations (red letters) at the periphery of the third β‐propeller domain of LRP4 compromise binding to MuSK, whereas SOS2 mutations (green letters) in the centre have no effect on agrin/LRP4/MuSK signalling. (a) Docking simulation of the β‐propeller domain of LRP6 (PDB ID, 2IEP), a homologue of LRP4, and the immunoglobulin‐like domains 1 and 2 of MuSK (PDB ID, 3SOV). The immunoglobulin‐like domain 1 of MuSK binds to the periphery of the third β‐propeller domain of LRP4. (b) Schematic of the agrin/LRP4/MuSK ternary complex. Agrin binds to the LDLa repeats 6–8, EGF‐like domains and the first β‐propeller domain close to the N‐terminal end of LRP4 (solid lines), as well as weakly to the third β‐propeller domain of LRP4 (dotted lines) (Zhang et al., ). MuSK binds to the 4th/5th LDLa repeats (solid line) as well as to the third β‐propeller domain (dotted line) (Zhang et al., ).

Figure 3.

Mutations in GFPT1, DPAGT1, ALG14 and ALG14 are identified in CMS, which encode enzymes in N‐linked glycosylation pathway. GFPT1 is a rate‐limiting enzyme to synthesise UDP‐GlcNAc, a source of multiple glycosylation processes including N‐ and O‐linked protein glycosylations. DPAG1 and ALG14 catalyse first two steps to add GlcNAc (blue circle) to dolichyl phosphate. ALG2 catalyses the second and third steps to add mannose (green circle). After translocation of dolichyl phosphate‐linked oligosaccharides across the ER membrane with flippase encoded by RFT1 (not shown) (Helenius et al., ) and addition of more mannoses (green circles) and glucoses (red circle) with the other ALG enzymes (not shown), the mature oligosaccharides are transferred to asparagine (N) on the target protein by oligosaccharyltransferase.

Figure 4.

Protein‐anchoring therapy for endplate AChE deficiency due to COLQ mutations. Intravenously introduced AAV8‐COLQ infects the skeletal muscle. Asymmetric A12‐AChE is excreted from the skeletal muscle and is targeted to the NMJ by specifically binding to perlecan and MuSK.

close

References

Aumailley M, Bruckner‐Tuderman L, Carter WG et al. (2005) A simplified laminin nomenclature. Matrix Biology 24: 326–332.

Banwell BL, Russel J, Fukudome T et al. (1999) Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. Journal of Neuropathology and Experimental Neurology 58: 832–846.

Basiri K, Belaya K, Liu WW et al. (2013) Clinical features in a large Iranian family with a limb‐girdle congenital myasthenic syndrome due to a mutation in DPAGT1. Neuromuscular Disorders 23: 469–472.

Beeson D, Higuchi O, Palace J et al. (2006) Dok‐7 mutations underlie a neuromuscular junction synaptopathy. Science 313: 1975–1978.

Belaya K, Finlayson S, Slater CR et al. (2012) Mutations in DPAGT1 cause a limb‐girdle congenital myasthenic syndrome with tubular aggregates. American Journal of Human Genetics 91: 193–201.

Ben Ammar A, Soltanzadeh P, Bauche S et al. (2013) A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. PloS One 8: e53826.

Bergamin E, Hallock PT, Burden SJ and Hubbard SR (2010) The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization. Molecular Cell 39: 100–109.

Bulman DE, Scoggan KA, van Oene MD et al. (1999) A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 53: 1932–1936.

Burden SJ, Yumoto N and Zhang W (2013) The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harbor Perspectives in Biology 5: a009167.

Cai Y, Cronin CN, Engel AG et al. (2004) Choline acetyltransferase structure reveals distribution of mutations that cause motor disorders. EMBO Journal 23: 2047–2058.

Cartaud A, Strochlic L, Guerra M et al. (2004) MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. Journal of Cell Biology 165: 505–515.

Charlesworth A, Gagnoux‐Palacios L, Bonduelle M et al. (2003) Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. Journal of Investigative Dermatology 121: 1344–1348.

Chevessier F, Faraut B, Ravel‐Chapuis A et al. (2004) MUSK, a new target for mutations causing congenital myasthenic syndrome. Human Molecular Genetics 13: 3229–3240.

Cossins J, Belaya K, Hicks D et al. (2013) Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain 136: 944–956.

Cossins J, Burke G, Maxwell S et al. (2006) Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain 129: 2773–2783.

Croxen R, Hatton C, Shelley C et al. (2002) Recessive inheritance and variable penetrance of slow‐channel congenital myasthenic syndromes. Neurology 59: 162–168.

Engel AG, Ohno K, Bouzat C, Sine SM and Griggs RC (1996) End‐plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. Annals of Neurology 40: 810–817.

Erickson JD, Varoqui H, Schafer MK et al. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a “cholinergic” gene locus. Journal of Biological Chemistry 269: 21929–21932.

Froehner SC, Luetje CW, Scotland PB and Patrick J (1990) The postsynaptic 43K protein clusters muscle nicotinic acetylcholine receptors in Xenopus oocytes. Neuron 5: 403–410.

Gao XD, Tachikawa H, Sato T, Jigami Y and Dean N (2005) Alg14 recruits Alg13 to the cytoplasmic face of the endoplasmic reticulum to form a novel bipartite UDP‐N‐acetylglucosamine transferase required for the second step of N‐linked glycosylation. Journal of Biological Chemistry 280: 36254–36262.

Gundesli H, Talim B, Korkusuz P et al. (2010) Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal‐recessive limb‐girdle muscular dystrophy. American Journal of Human Genetics 87: 834–841.

Hallock PT, Xu CF, Park TJ et al. (2010) Dok‐7 regulates neuromuscular synapse formation by recruiting Crk and Crk‐L. Genes & Development 24: 2451–2461.

Hasselbacher K, Wiggins RC, Matejas V et al. (2006) Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2‐associated disorders. Kidney International 70: 1008–1012.

Helenius J, Ng DT, Marolda CL et al. (2002) Translocation of lipid‐linked oligosaccharides across the ER membrane requires Rft1 protein. Nature 415: 447–450.

Hoffmann K, Muller JS, Stricker S et al. (2006) Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. American Journal of Human Genetics 79: 303–312.

Huh SY, Kim HS, Jang HJ, Park YE and Kim DS (2012) Limb‐girdle myasthenia with tubular aggregates associated with novel GFPT1 mutations. Muscle & Nerve 46: 600–604.

Huze C, Bauche S, Richard P et al. (2009) Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. American Journal of Human Genetics 85: 155–167.

Ito M, Suzuki Y, Okada T et al. (2012) Protein‐anchoring strategy for delivering acetylcholinesterase to the neuromuscular junction. Molecular Therapy 20: 1384–1392.

Kimbell LM, Ohno K, Engel AG and Rotundo RL (2004) C‐terminal and heparin‐binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse. Journal of Biological Chemistry 279: 10997–11005.

Krejci E, Thomine S, Boschetti N et al. (1997) The mammalian gene of acetylcholinesterase‐associated collagen. Journal of Biological Chemistry 272: 22840–22847.

Lee Y, Rudell J, Yechikhov S et al. (2008) Rapsyn carboxyl terminal domains mediate muscle specific kinase‐induced phosphorylation of the muscle acetylcholine receptor. Neuroscience 153: 997–1007.

Lerche H, Heine R, Pika U et al. (1993) Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III–IV linker. Journal of Physiology 470: 13–22.

Leupin O, Piters E, Halleux C et al. (2011) Bone overgrowth‐associated mutations in the LRP4 gene impair sclerostin facilitator function. Journal of Biological Chemistry 286: 19489–19500.

Li Y, Pawlik B, Elcioglu N et al. (2010) LRP4 mutations alter Wnt/beta‐catenin signaling and cause limb and kidney malformations in Cenani–Lenz syndrome. American Journal of Human Genetics 86: 696–706.

Maselli RA, Arredondo J, Cagney O et al. (2010) Mutations in MUSK causing congenital myasthenic syndrome impair MuSK‐Dok‐7 interaction. Human Molecular Genetics 19: 2370–2379.

Maselli RA, Arredondo J, Cagney O et al. (2011) Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clinical Genetics 80: 444–451.

Maselli RA, Fernandez JM, Arredondo J et al. (2012) LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non‐neural (z‐) agrin. Human Genetics 131: 1123–1135.

Maselli RA, Ng JJ, Anderson JA et al. (2009) Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. Journal of Medical Genetics 46: 203–208.

Michalk A, Stricker S, Becker J et al. (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. American Journal of Human Genetics 82: 464–476.

Milone M, Shen XM, Selcen D et al. (2009) Myasthenic syndrome due to defects in rapsyn: clinical and molecular findings in 39 patients. Neurology 73: 228–235.

Milone M, Wang H‐L, Ohno K et al. (1998) Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. Neuron 20: 575–588.

Mishina M, Takai T, Imoto K et al. (1986) Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. Nature 321: 406–411.

Morgan NV, Brueton LA, Cox P et al. (2006) Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. American Journal of Human Genetics 79: 390–395.

Muller JS, Abicht A, Burke G et al. (2004) The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo‐European founder. Journal of Medical Genetics 41: e104.

Nakata T, Ito M, Azuma Y et al. (2013) Mutations in the C‐terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ‐MuSK interaction. Human Mutation 34: 997–1004.

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 Research Molecular Brain Research 16: 287–294.

Ohkawara B, Cabrera-Serrano M, Nakata T et al. (2014) LRP4 third beta‐propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position‐specific manner. Human Molecular Genetics 23: 1856–1868.

Ohno K, Anlar B and Engel AG (1999) Congenital myasthenic syndrome caused by a mutation in the Ets‐binding site of the promoter region of the acetylcholine receptor epsilon subunit gene. Neuromuscular Disorders 9: 131–135.

Ohno K, Brengman J, Tsujino A and Engel AG (1998) Human endplate acetylcholinesterase deficiency caused by mutations in the collagen‐like tail subunit (ColQ) of the asymmetric enzyme. Proceedings of the National Academy of Sciences of the USA 95: 9654–9659.

Ohno K, Brengman JM, Felice KJ, Cornblath DR and Engel AG (1999) Congenital end‐plate acetylcholinesterase deficiency caused by a nonsense mutation and an A‐‐>G splice‐donor‐site mutation at position +3 of the collagenlike‐tail‐subunit gene (COLQ): how does G at position +3 result in aberrant splicing? American Journal of Human Genetics 65: 635–644.

Ohno K and Engel AG (2004) Lack of founder haplotype for the rapsyn N88K mutation: N88K is an ancient founder mutation or arises from multiple founders. Journal of Medical Genetics 41: e8.

Ohno K, Engel AG, Brengman JM et al. (2000) The spectrum of mutations causing endplate acetylcholinesterase deficiency. Annals of Neurology 47: 162–170.

Ohno K, Engel AG, Shen XM et al. (2002) Rapsyn mutations in humans cause endplate acetylcholine‐receptor deficiency and myasthenic syndrome. American Journal of Human Genetics 70: 875–885.

Ohno K, Hutchinson DO, Milone M et al. (1995) Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proceedings of the National Academy of Sciences of the USA 92: 758–762.

Ohno K, Quiram PA, Milone M et al. (1997) Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. Human Molecular Genetics 6: 753–766.

Ohno K, Sadeh M, Blatt I, Brengman JM and Engel AG (2003) E‐box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Human Molecular Genetics 12: 739–748.

Ohno K, Tsujino A, Brengman JM et al. (2001) Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proceedings of the National Academy of Sciences of the USA 98: 2017–2022.

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

Okada K, Inoue A, Okada M et al. (2006) The muscle protein Dok‐7 is essential for neuromuscular synaptogenesis. Science 312: 1802–1805.

Okuda T, Haga T, Kanai Y et al. (2000) Identification and characterization of the high‐affinity choline transporter. Nature Neuroscience 3: 120–125.

Peng HB, Xie H, Rossi SG and Rotundo RL (1999) Acetylcholinesterase clustering at the neuromuscular junction involves perlecan and dystroglycan. Journal of Cell Biology 145: 911–921.

Ptacek LJ, George AL Jr, Barchi RL et al. (1992) Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8: 891–897.

Ptacek LJ, George AL Jr, Griggs RC et al. (1991) Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67: 1021–1027.

Schara U, Christen HJ, Durmus H et al. (2010) Long‐term follow‐up in patients with congenital myasthenic syndrome due to CHAT mutations. European Journal of Paediatric Neurology 14: 326–333.

Selcen D, Juel VC, Hobson‐Webb LD et al. (2011) Myasthenic syndrome caused by plectinopathy. Neurology 76: 327–336.

Selcen D, Milone M, Shen XM et al. (2008) Dok‐7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Annals of Neurology 64: 71–87.

Selcen D, Shen XM, Milone M et al. (2013) GFPT1‐myasthenia: clinical, structural, and electrophysiologic heterogeneity. Neurology 81: 370–378.

Senderek J, Muller JS, Dusl M et al. (2011) Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. American Journal of Human Genetics 88: 162–172.

Shelley C and Colquhoun D (2005) A human congenital myasthenia‐causing mutation (epsilonL78P) of the muscle nicotinic acetylcholine receptor with unusual single channel properties. Journal of Physiology 564: 377–396.

Shen XM, Crawford TO, Brengman J et al. (2011) Functional consequences and structural interpretation of mutations of human choline acetyltransferase. Human Mutation 32: 1259–1267.

Shen XM, Fukuda T, Ohno K, Sine SM and Engel AG (2008) Congenital myasthenia‐related AChR delta subunit mutation interferes with intersubunit communication essential for channel gating. Journal of Clinical Investigation 118: 1867–1876.

Shen XM, Ohno K, Sine SM and Engel AG (2005) Subunit‐specific contribution to agonist binding and channel gating revealed by inherited mutation in muscle acetylcholine receptor M3–M4 linker. Brain 128: 345–355.

Shen X‐M, Ohno K, Tsujino A et al. (2003) Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating. Journal of Clinical Investigation 111: 497–505.

Sigoillot SM, Bourgeois F, Lambergeon M, Strochlic L and Legay C (2010) ColQ controls postsynaptic differentiation at the neuromuscular junction. Journal of Neuroscience 30: 13–23.

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

Sine SM, Shen X‐M, Wang H‐L et al. (2002) Naturally occurring mutations at the acetylcholine receptor binding site independently alter ACh binding and channel gating. Journal of General Physiology 120: 483–496.

Smith FJ, Eady RA, Leigh IM et al. (1996) Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nature Genetics 13: 450–457.

Thiel C, Schwarz M, Peng J et al. (2003) A new type of congenital disorders of glycosylation (CDG‐II) provides new insights into the early steps of dolichol‐linked oligosaccharide biosynthesis. Journal of Biological Chemistry 278: 22498–22505.

Tsujino A, Maertens C, Ohno K et al. (2003) Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proceedings of the National Academy of Sciences of the USA 100: 7377–7382.

Wang H‐L, Milone M, Ohno K et al. (1999) Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. Nature Neuroscience 2: 226–233.

Wang H‐L, Ohno K, Milone M et al. (2000) Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. Journal of General Physiology 116: 449–462.

Wu X, Rush JS, Karaoglu D et al. (2003) Deficiency of UDP‐GlcNAc:dolichol phosphate N‐acetylglucosamine‐1 phosphate transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. Human Mutation 22: 144–150.

Zenker M, Aigner T, Wendler O et al. (2004) Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Human Molecular Genetics 13: 2625–2632.

Zhang W, Coldefy AS, Hubbard SR and Burden SJ (2011) 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). Journal of Biological Chemistry 286: 40624–40630.

Zong Y, Zhang B, Gu S et al. (2012) Structural basis of agrin‐LRP4‐MuSK signaling. Genes & Development 26: 247–258.

Zuber B and Unwin N (2013) Structure and superorganization of acetylcholine receptor‐rapsyn complexes. Proceedings of the National Academy of Sciences of the USA 110: 10622–10627.

Further Reading

Burden SJ (2011) SnapShot: neuromuscular junction. Cell 144: 826–826, e821.

Engel AG (2012) Current status of the congenital myasthenic syndromes. Neuromuscular Disorders 22: 99–111.

Engel AG, Ohno K and Sine SM (2004) Congenital myasthenic syndromes. In: Engel AG and Franzini‐Armstrong C (eds) Myology, 3rd edn. pp. 1801–1844. New York: McGraw Hill.

Finlayson S, Beeson D and Palace J (2013) Congenital myasthenic syndromes: an update. Practical Neurology 13: 80–91.

Gilhus NE (2012) Myasthenia and the neuromuscular junction. Current Opinion in Neurology 25: 523–529.

Ohno K, Ito M and Engel AG (2012) Congenital myasthenic syndromes – molecular bases of congenital defects of proteins at the neuromuscular junction. In: Zaher A (ed.) Neuromuscular Disorders, pp. 175–200. Rijeka: InTech.

Wu H, Xiong WC and Mei L (2010) To build a synapse: signaling pathways in neuromuscular junction assembly. Development 137: 1017–1033.

Zong Y and Jin R (2013) Structural mechanisms of the agrin‐LRP4‐MuSK signaling pathway in neuromuscular junction differentiation. Cellular and Molecular Life Sciences 70: 3077–3088.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Ohno, Kinji, Ohkawara, Bisei, Ito, Mikako, and Engel, Andrew G(May 2014) Molecular Genetics of Congenital Myasthenic Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024314]