ArticleNeurology2012
Highly fatal fast-channel syndrome caused by AChR ε subunit mutation at the agonist binding site.
Article in Neurology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 2 of them syntheses that pooled it.
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Who cites it
13 citing papers in PubMed, 2 syntheses or guidelines pooled it, 32 citations in OpenAlex.
- Pharmacological Strategy for Congenital Myasthenic Syndrome with CHRNE Mutations: A Meta-Analysis of Case Reports.Current neuropharmacology · 2021Pooled it
- Congenital myasthenic syndromes.Orphanet journal of rare diseases · 2019Pooled it
- Article
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Article
- A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family.Chinese medical journal · 2016Article
- Article
- Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment.The Lancet. Neurology · 2015Review
- Inherited disorders of the neuromuscular junction: an update.Journal of neurology · 2014Review
- New horizons for congenital myasthenic syndromes.Annals of the New York Academy of Sciences · 2012Review
- Congenital myasthenic syndromes in 2012.Current neurology and neuroscience reports · 2012Review
- Current status of the congenital myasthenic syndromes.Neuromuscular disorders : NMD · 2012Review
- A Novel Homozygous Variant in the CHRNE Gene in 2 Siblings with Congenital Myasthenic Syndrome.Child neurology openArticle
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5 authors at 1 institution in 1 country.
Funding
Abstract
objectiveTo characterize the molecular basis of a novel fast-channel congenital myasthenic syndrome.
methodsWe used the candidate gene approach to identify the pathogenic mutation in the acetylcholine receptor (AChR) ε subunit, genetically engineered the mutant AChR into HEK cells, and evaluated the level of expression and kinetic properties of the mutant receptor.
resultsAn 8-year-old boy born to consanguineous parents had severe myasthenic symptoms since birth. He is wheelchair bound and pyridostigmine therapy enables him to take only a few steps. Three similarly affected siblings died in infancy. He carries a homozygous p.W55R mutation at the α/ε subunit interface of the AChR agonist binding site. The mutant protein expresses well in HEK cells. Patch-clamp analysis of the mutant receptor expressed in HEK cells reveals 30-fold reduced apparent agonist affinity, 75-fold reduced apparent gating efficiency, and strikingly attenuated channel opening probability (P(open)) over a range agonist concentrations.
conclusionIntroduction of a cationic Arg into the anionic environment of α/ε AChR binding site hinders stabilization of cationic ACh by aromatic residues and accounts for the markedly perturbed kinetic properties of the receptor. The very low P(open) explains the poor response to pyridostigmine and the high fatality of the disease.
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