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Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome
Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree ha...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151691/ https://www.ncbi.nlm.nih.gov/pubmed/35642635 http://dx.doi.org/10.1172/JCI159002 |
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author | Ramirez-Martinez, Andres Zhang, Yichi van den Boogaard, Marie-Jose McAnally, John R. Rodriguez-Caycedo, Cristina Chai, Andreas C. Chemello, Francesco Massink, Maarten P.G. Cuppen, Inge Elferink, Martin G. van Es, Robert J.J. Janssen, Nard G. Walraven-van Oijen, Linda P.A.M. Liu, Ning Bassel-Duby, Rhonda van Jaarsveld, Richard H. Olson, Eric N. |
author_facet | Ramirez-Martinez, Andres Zhang, Yichi van den Boogaard, Marie-Jose McAnally, John R. Rodriguez-Caycedo, Cristina Chai, Andreas C. Chemello, Francesco Massink, Maarten P.G. Cuppen, Inge Elferink, Martin G. van Es, Robert J.J. Janssen, Nard G. Walraven-van Oijen, Linda P.A.M. Liu, Ning Bassel-Duby, Rhonda van Jaarsveld, Richard H. Olson, Eric N. |
author_sort | Ramirez-Martinez, Andres |
collection | PubMed |
description | Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9–mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases. |
format | Online Article Text |
id | pubmed-9151691 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-91516912022-06-02 Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome Ramirez-Martinez, Andres Zhang, Yichi van den Boogaard, Marie-Jose McAnally, John R. Rodriguez-Caycedo, Cristina Chai, Andreas C. Chemello, Francesco Massink, Maarten P.G. Cuppen, Inge Elferink, Martin G. van Es, Robert J.J. Janssen, Nard G. Walraven-van Oijen, Linda P.A.M. Liu, Ning Bassel-Duby, Rhonda van Jaarsveld, Richard H. Olson, Eric N. J Clin Invest Research Article Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9–mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases. American Society for Clinical Investigation 2022-06-01 2022-06-01 /pmc/articles/PMC9151691/ /pubmed/35642635 http://dx.doi.org/10.1172/JCI159002 Text en © 2022 Ramirez-Martinez et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Ramirez-Martinez, Andres Zhang, Yichi van den Boogaard, Marie-Jose McAnally, John R. Rodriguez-Caycedo, Cristina Chai, Andreas C. Chemello, Francesco Massink, Maarten P.G. Cuppen, Inge Elferink, Martin G. van Es, Robert J.J. Janssen, Nard G. Walraven-van Oijen, Linda P.A.M. Liu, Ning Bassel-Duby, Rhonda van Jaarsveld, Richard H. Olson, Eric N. Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title | Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title_full | Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title_fullStr | Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title_full_unstemmed | Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title_short | Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome |
title_sort | impaired activity of the fusogenic micropeptide myomixer causes myopathy resembling carey-fineman-ziter syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9151691/ https://www.ncbi.nlm.nih.gov/pubmed/35642635 http://dx.doi.org/10.1172/JCI159002 |
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