A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.

TitleA defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.
Publication TypeJournal Article
Year of Publication2017
AuthorsDi Gioia, SAlessandro, Connors, S, Matsunami, N, Cannavino, J, Rose, MF, Gilette, NM, Artoni, P, Sobreira, NLygia de M, Chan, W-M, Webb, BD, Robson, CD, Cheng, L, Van Ryzin, C, Ramirez-Martinez, A, Mohassel, P, Leppert, M, Scholand, MBeth, Grunseich, C, Ferreira, CR, Hartman, T, Hayes, IM, Morgan, T, Markie, DM, Fagiolini, M, Swift, A, Chines, PS, Speck-Martins, CE, Collins, FS, Jabs, EWang, Bönnemann, CG, Olson, EN, Carey, JC, Robertson, SP, Manoli, I, Engle, EC
Corporate AuthorsMoebius Syndrome Research Consortium
JournalNat Commun
Date Published2017 07 06
KeywordsAdult, Amino Acid Sequence, Animals, Cell Fusion, Child, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Expression, Genes, Recessive, Genetic Complementation Test, Humans, Infant, Male, Membrane Proteins, Mobius Syndrome, Morphogenesis, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Myoblasts, Pedigree, Pierre Robin Syndrome, Sequence Alignment, Sequence Homology, Amino Acid, Zebrafish, Zebrafish Proteins

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

Alternate JournalNat Commun
PubMed ID28681861
PubMed Central IDPMC5504296
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U01 HD079068 / HD / NICHD NIH HHS / United States
K08 NS099502 / NS / NINDS NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States