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

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 ?-subunit. We here report a 16-year-old patient harboring a novel ?L273F mutation (?L294F in HGVS nomenclature) in the second transmembrane domain (M2) of the AChR ? subunit. Kinetic analyses with ACh and the weak agonist choline indicate that ?L273F prolongs the channel opening bursts 9.4-fold due to a 75-fold increase in channel gating efficiency, whereas a previously identified ?L269F mutation (?L289F in HGVS nomenclature) at an equivalent location in the AChR ?-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 ? and ? subunit and nearby M2 domain residues in neighboring ? subunits contribute to structural stability of the open relative to the closed channel states. INTERPRETATION:The greater increase in gating efficiency by ?L273F than by ?L269F explains why ?L273F has more severe clinical effects. Both ?L273F and ?L269F impair channel gating by disrupting hydrophobic interactions with neighboring ?-subunits. Differences in the extent of impairment of channel gating in ? and ? mutant receptors suggest unequal contributions of ?/? and ?/? subunit pairs to gating efficiency.

SUBMITTER: Shen XM 

PROVIDER: S-EPMC6801167 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature