Molecular Genetics of Congenital Myasthenic Syndromes

AbstractCongenital 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,CHRNDandCHRNE); skeletal muscle sodium channel (SCN4A); signalling molecules driving AChR clustering and subserving maintenance and differentiation of the postsynaptic region (AGRN, LRP4, MUSKandDOK7); postsynaptic structural proteins (RAPSNandPLEC); synaptic β2 laminin, which promotes presynaptic differentiation, and synaptic collagen Q; presynaptic choline acetyltransferase and enzymes in subserving protein glycosylation (GFPT1,DPAGT1,ALG14, andALG2). 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 theN‐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 ofColq‐knockout mice.Mutations in choline acetyltransferase (ChAT) cause defective resynthesis of ACh at the nerve terminal and a CMS associated with frequent episodic apnoea.