Congenital myasthenic syndromes caused by mutations in acetylcholine receptor genes

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. According to the site of the primary defect, the CMS can be classified as presynaptic, synaptic, or postsynaptic. The postsynaptic CMS identified to date are characterized by a kinetic abnormality of the acetylcholine receptor (AChR) with or without AChR deficiency, or by AChR deficiency without a primary kinetic abnormality. We hypothesized and subsequently confirmed that a kinetic abnormality of the AChR at the single-channel level predicts a mutation in an AChR subunit gene, and that a severe deficiency of AChR can stem from nonsense mutations in AChR subunit genes. Seven dominant slow-channel mutations in different subunits and different domains of the subunits have been identified thus far. Mutations in the M2 and M1 transmembrane domains act predominantly by slowing channel closure, and mutations in M2 also allow spontaneous channel opening. Another slow-channel mutation in the extracellular domain of the α-subunit acts predominantly by enhancing the affinity of AChR for ACh, causing repeated channel reopenings during a prolonged ACh occupancy. The recently discovered low-affinity fast-channel syndrome is the physiologic opposite of the slow-channel syndrome. Here, a mutation in the extracellular domain of the ε-subunit reduces the affinity of AChR for ACh; this decreases the rate of channel opening, and results in briefer than normal bursts of openings. Finally, a number of homozygous or heterozygous nonsense mutations in an AChR subunit cause severe AChR deficiency.