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 Pg; Cuppen, Inge; Elferink, Martin G; van Es, Robert Jj; Janssen, Nard G; Walraven-van Oijen, Linda Pam; Liu, Ning; Bassel-Duby, Rhonda; van Jaarsveld, Richard H; Olson, Eric N
(2022) Journal of Clinical Investigation, volume 132, issue 11, pp. 1 - 11
(Article)
Abstract
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
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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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Keywords: Animals, Humans, Membrane Proteins/genetics, Mice, Mobius Syndrome, Muscle Proteins/genetics, Muscular Diseases/genetics, Pierre Robin Syndrome, General Medicine, Journal Article
ISSN: 0021-9738
Publisher: The American Society for Clinical Investigation
Note: Funding Information: We thank J. Cabrera for graphics, and L. Guo and L. Xi for bio-informatics analysis. We thank our colleagues M.C. Kruijt, S.G. Kant, E.H. Niks, and W. van Hecke for expert advice. We thank G.A. Garry for expert clinical advice. We thank the following Core Facilities at the University of Texas Southwestern Medical Center: the Molecular Pathology Core under the direction of B. Evers, the Electron Microscopy Core under the direction of K. Luby-Phelps, and the Children’s Medical Center Research Sequencing facility under the direction of J. Xu. We thank the following facilities at the University Medical Center Utrecht: Bioinformatics under the supervision of H. van Deutekom and Genome Diagnostics under the direction of H.K. Ploos van Amstel. This work was supported by grants from the NIH (HL130253 and HD087351) and the Robert A. Welch Foundation (1-0025) to ENO. Publisher Copyright: © 2022, Ramirez-Martinez et al.
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