A Defect in Myoblast Fusion Underlies Carey-Fineman-Ziter Syndrome

Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

Abstract

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 mymkinsT/insT 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • 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 / deficiency
  • Membrane Proteins / genetics*
  • Mobius Syndrome / genetics*
  • Mobius Syndrome / metabolism
  • Mobius Syndrome / pathology
  • Morphogenesis / genetics*
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics*
  • Muscle, Skeletal / growth & development
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Diseases / genetics*
  • Muscular Diseases / metabolism
  • Muscular Diseases / pathology
  • Mutation*
  • Myoblasts / metabolism*
  • Myoblasts / pathology
  • Pedigree
  • Pierre Robin Syndrome / genetics*
  • Pierre Robin Syndrome / metabolism
  • Pierre Robin Syndrome / pathology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Zebrafish
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics*

Substances

  • MYMK protein, human
  • Membrane Proteins
  • Muscle Proteins
  • Zebrafish Proteins
  • mymk protein, zebrafish

Supplementary concepts

  • Myopathy, congenital nonprogressive with Moebius and Robin sequences