| Autor: |
Xin‐Ming Shen, Margherita Milone, Hang‐Long Wang, Brenda Banwell, Duygu Selcen, Steven M. Sine, Andrew G. Engel |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Annals of Clinical and Translational Neurology, Vol 6, Iss 10, Pp 2066-2078 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2328-9503 |
| DOI: |
10.1002/acn3.50902 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
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