ArticleThe Journal of clinical investigation2012
Myasthenic syndrome AChRα C-loop mutant disrupts initiation of channel gating.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 25 citations in OpenAlex.
- Article
- Disentangling the mechanistic role of loop-C capping in Cys-loop receptor activation.Nature communications · 2025Article
- Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia.Annals of clinical and translational neurology · 2023Article
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR.The Journal of general physiology · 2016Article
- Article
- The atypical cation-conduction and gating properties of ELIC underscore the marked functional versatility of the pentameric ligand-gated ion-channel fold.The Journal of general physiology · 2015Article
- Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.The Lancet. Neurology · 2015Review
- Inherited disorders of the neuromuscular junction: an update.Journal of neurology · 2014Review
- LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner.Human molecular genetics · 2014Article
- Article
- New horizons for congenital myasthenic syndromes.Annals of the New York Academy of Sciences · 2012Review
- Pharmacogenomics: mapping monogenic mutations to direct therapy.The Journal of clinical investigation · 2012Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Congenital myasthenic syndromes (CMSs) are neuromuscular disorders that can be caused by defects in ace-tylcholine receptor (AChR) function. Disease-associated point mutants can reveal the unsuspected functional significance of mutated residues. We identified two pathogenic mutations in the extracellular domain of the AChR α subunit (AChRα) in a patient with myasthenic symptoms since birth: a V188M mutation in the C-loop and a heteroallelic G74C mutation in the main immunogenic region. The G74C mutation markedly reduced surface AChR expression in cultured cells, whereas the V188M mutant was expressed robustly but had severely impaired kinetics. Single-channel patch-clamp analysis indicated that V188M markedly decreased the apparent AChR channel opening rate and gating efficiency. Mutant cycle analysis of energetic coupling among conserved residues within or dispersed around the AChRα C-loop revealed that V188 is functionally linked to Y190 in the C-loop and to D200 in β-strand 10, which connects to the M1 transmembrane domain. Furthermore, V188M weakens inter-residue coupling of K145 in β-strand 7 with Y190 and with D200. Cumulatively, these results indicate that V188 of AChRα is part of an interdependent tetrad that contributes to rearrangement of the C-loop during the initial coupling of agonist binding to channel gating.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.