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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
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.
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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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