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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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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. |
format | Online Article Text |
id | pubmed-10187723 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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