Molecular Genetics of Congenital Myasthenic Syndromes


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 AAV8COLQ infects the skeletal muscle. Asymmetric A12AChE is excreted from the skeletal muscle and is targeted to the NMJ by specifically binding to perlecan and MuSK.



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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.

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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. [doi: 10.1002/9780470015902.a0024314]