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Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia

OBJECTIVE: To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS). METHODS: Whole...

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Autores principales: Shen, Xin‐Ming, Nakata, Tomohiko, Mizuno, Seiji, Imoto, Issei, Selcen, Duygu, Ohno, Kinji, Engel, Andrew G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187723/
https://www.ncbi.nlm.nih.gov/pubmed/36891870
http://dx.doi.org/10.1002/acn3.51756
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author Shen, Xin‐Ming
Nakata, Tomohiko
Mizuno, Seiji
Imoto, Issei
Selcen, Duygu
Ohno, Kinji
Engel, Andrew G.
author_facet Shen, Xin‐Ming
Nakata, Tomohiko
Mizuno, Seiji
Imoto, Issei
Selcen, Duygu
Ohno, Kinji
Engel, Andrew G.
author_sort Shen, Xin‐Ming
collection PubMed
description OBJECTIVE: To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS). METHODS: Whole exome sequencing, α‐bungarotoxin binding assay, single channel patch‐clamp recordings, and maximum likelihood analysis of channel kinetics. RESULTS: We identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1–3) and three CMS patients (4–6), respectively. Each Escobar syndrome patient carries γP121R along with γV221Afs*44 in patients 1 and 2, and γY63* in patient 3. Three CMS patients share εP121T along with εR20W, εG‐8R, and εY15H in patients 4, 5, and 6, respectively. Surface expressions of γP121R‐ and εP121T‐AChR were 80% and 138% of the corresponding wild‐type AChR, whereas εR20W, εG‐8R, and εY15H reduced receptor expression to 27%, 35%, and 30% of wild‐type εAChR, respectively. γV221Afs*44 and γY63* are null variants. Thus, γP121R and εP121T determine the phenotype. γP121R and εP121T shorten channel opening burst duration to 28% and 18% of corresponding wild‐type AChR by reducing the channel gating equilibrium constant 44‐ and 63‐fold, respectively. INTERPRETATION: Similar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine‐binding site of the AChR γ and ε subunits causes Escobar syndrome without pterygium and fast‐channel CMS, respectively, suggesting that therapy for the fast‐channel CMS will benefit Escobar syndrome.
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spelling pubmed-101877232023-05-17 Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia Shen, Xin‐Ming Nakata, Tomohiko Mizuno, Seiji Imoto, Issei Selcen, Duygu Ohno, Kinji Engel, Andrew G. Ann Clin Transl Neurol Research Articles OBJECTIVE: To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS). METHODS: Whole exome sequencing, α‐bungarotoxin binding assay, single channel patch‐clamp recordings, and maximum likelihood analysis of channel kinetics. RESULTS: We identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1–3) and three CMS patients (4–6), respectively. Each Escobar syndrome patient carries γP121R along with γV221Afs*44 in patients 1 and 2, and γY63* in patient 3. Three CMS patients share εP121T along with εR20W, εG‐8R, and εY15H in patients 4, 5, and 6, respectively. Surface expressions of γP121R‐ and εP121T‐AChR were 80% and 138% of the corresponding wild‐type AChR, whereas εR20W, εG‐8R, and εY15H reduced receptor expression to 27%, 35%, and 30% of wild‐type εAChR, respectively. γV221Afs*44 and γY63* are null variants. Thus, γP121R and εP121T determine the phenotype. γP121R and εP121T shorten channel opening burst duration to 28% and 18% of corresponding wild‐type AChR by reducing the channel gating equilibrium constant 44‐ and 63‐fold, respectively. INTERPRETATION: Similar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine‐binding site of the AChR γ and ε subunits causes Escobar syndrome without pterygium and fast‐channel CMS, respectively, suggesting that therapy for the fast‐channel CMS will benefit Escobar syndrome. John Wiley and Sons Inc. 2023-03-09 /pmc/articles/PMC10187723/ /pubmed/36891870 http://dx.doi.org/10.1002/acn3.51756 Text en © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Shen, Xin‐Ming
Nakata, Tomohiko
Mizuno, Seiji
Imoto, Issei
Selcen, Duygu
Ohno, Kinji
Engel, Andrew G.
Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title_full Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title_fullStr Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title_full_unstemmed Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title_short Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia
title_sort impaired gating of γ‐ and ε‐achr respectively causes escobar syndrome and fast‐channel myasthenia
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187723/
https://www.ncbi.nlm.nih.gov/pubmed/36891870
http://dx.doi.org/10.1002/acn3.51756
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