Slow-channel myasthenia due to novel mutation in M2 domain of AChR delta subunit

Xin Ming Shen, Margherita Milone, Hang Long Wang, Brenda Banwell, Duygu Selcen, Steven M. Sine, Andrew G. Engel

Research output: Contribution to journalArticle

Abstract

Objective: To characterize the molecular and phenotypic basis of a severe slow-channel congenital myasthenic syndrome (SCCMS). Methods: Intracellular and single-channel recordings from patient endplates; alpha-bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure. Results: Among 24 variants reported to cause SCCMS only two appear in the AChR δ-subunit. We here report a 16-year-old patient harboring a novel δL273F mutation (δL294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR δ subunit. Kinetic analyses with ACh and the weak agonist choline indicate that δL273F prolongs the channel opening bursts 9.4-fold due to a 75-fold increase in channel gating efficiency, whereas a previously identified εL269F mutation (εL289F in HGVS nomenclature) at an equivalent location in the AChR ε-subunit prolongs channel opening bursts 4.4-fold due to a 30-fold increase in gating efficiency. Structural modeling of AChR predicts that inter-helical hydrophobic interactions between the mutant residue in the δ and ε subunit and nearby M2 domain residues in neighboring α subunits contribute to structural stability of the open relative to the closed channel states. Interpretation: The greater increase in gating efficiency by δL273F than by εL269F explains why δL273F has more severe clinical effects. Both δL273F and εL269F impair channel gating by disrupting hydrophobic interactions with neighboring α-subunits. Differences in the extent of impairment of channel gating in δ and ε mutant receptors suggest unequal contributions of ε/α and δ/α subunit pairs to gating efficiency.

Original languageEnglish (US)
Pages (from-to)2066-2078
Number of pages13
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2019

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Congenital Myasthenic Syndromes
Hydrophobic and Hydrophilic Interactions
Terminology
Activation Analysis
Bungarotoxins
Mutation
Choline
Microsatellite Repeats
Genes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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Slow-channel myasthenia due to novel mutation in M2 domain of AChR delta subunit. / Shen, Xin Ming; Milone, Margherita; Wang, Hang Long; Banwell, Brenda; Selcen, Duygu; Sine, Steven M.; Engel, Andrew G.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 10, 01.10.2019, p. 2066-2078.

Research output: Contribution to journalArticle

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AU - Shen, Xin Ming

AU - Milone, Margherita

AU - Wang, Hang Long

AU - Banwell, Brenda

AU - Selcen, Duygu

AU - Sine, Steven M.

AU - Engel, Andrew G.

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AB - Objective: To characterize the molecular and phenotypic basis of a severe slow-channel congenital myasthenic syndrome (SCCMS). Methods: Intracellular and single-channel recordings from patient endplates; alpha-bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure. Results: Among 24 variants reported to cause SCCMS only two appear in the AChR δ-subunit. We here report a 16-year-old patient harboring a novel δL273F mutation (δL294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR δ subunit. Kinetic analyses with ACh and the weak agonist choline indicate that δL273F prolongs the channel opening bursts 9.4-fold due to a 75-fold increase in channel gating efficiency, whereas a previously identified εL269F mutation (εL289F in HGVS nomenclature) at an equivalent location in the AChR ε-subunit prolongs channel opening bursts 4.4-fold due to a 30-fold increase in gating efficiency. Structural modeling of AChR predicts that inter-helical hydrophobic interactions between the mutant residue in the δ and ε subunit and nearby M2 domain residues in neighboring α subunits contribute to structural stability of the open relative to the closed channel states. Interpretation: The greater increase in gating efficiency by δL273F than by εL269F explains why δL273F has more severe clinical effects. Both δL273F and εL269F impair channel gating by disrupting hydrophobic interactions with neighboring α-subunits. Differences in the extent of impairment of channel gating in δ and ε mutant receptors suggest unequal contributions of ε/α and δ/α subunit pairs to gating efficiency.

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