Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

Andres Ramirez-Martinez, Yichi Zhang, Marie Jose van den Boogaard, John R. McAnally, Cristina Rodriguez-Caycedo, Andreas C. Chai, Francesco Chemello, Maarten P.G. Massink, Inge Cuppen, Martin G. Elferink, Robert J.J. van Es, Nard G. Janssen, Linda P.A.M. Walraven-Van Oijen, Ning Liu, Rhonda Bassel-Duby, Richard H. van Jaarsveld, Eric N. Olson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere159002
JournalJournal of Clinical Investigation
Issue number11
StatePublished - Jun 1 2022

ASJC Scopus subject areas

  • Medicine(all)


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