Mutations in Different Functional Domains of the Human Muscle Acetylcholine Receptor Subunit in Patients with the Slow-Channel congenital Myasthenic Syndrome

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Abstract
Congenital myasthenic syndromes are a group of rare genetic disorders that compromise neuromuscular transmission. A subset of these disorders, the slow-channel congenital myasthenic syndrome (SCCMS), is dominantly inherited and has been shown to involve mutations within the muscle acetylcholine receptor (AChR). We have identified three new SCCMS mutations and a further familial case of the αG153S mutation. Single channel recordings from wild-type and mutant human AChR expressed in Xenopus oocytes demonstrate that each mutation prolongs channel activation episodes. The novel mutations αV156M, αT254I and αS269I are in different functional domains of the AChR αsubunit. Whereas αT254I is in the pore-lining region, like five of six previously reported SCCMS mutations, αS269I and αV156M are in extracellular domains. αS269I lies within the short extracellular sequence between M2 and M3, and identifies a new region of muscle AChR involved in ACh binding/channel gating. αV156M, although located close to αG153S which has been shown to increase ACh binding affinity, appears to alter channel function through a different molecular mechanism. Our results demonstrate heterogeneity in the SCCMS, indicate new regions of the AChR involved in ACh binding/channel gating and highlight the potential role of mutations outside the pore-lining regions in altering channel function in other ion channel disorders.