2. Academic Validation
  3. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

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

  • Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.
Silvio Alessandro Di Gioia 1 2 3,  Samantha Connors 4,  Norisada Matsunami 5,  Jessica Cannavino 6,  Matthew F Rose 1 2 7 8 9 10,  Nicole M Gilette 1 2,  Pietro Artoni 1 2 3,  Nara Lygia de Macena Sobreira 11,  Wai-Man Chan 1 2 3 12,  Bryn D Webb 13,  Caroline D Robson 14 15,  Long Cheng 1 2 3,  Carol Van Ryzin 16,  Andres Ramirez-Martinez 6,  Payam Mohassel 17 18,  Mark Leppert 5,  Mary Beth Scholand 19,  Christopher Grunseich 18,  Carlos R Ferreira 16,  Tyler Hartman 20,  Ian M Hayes 21,  Tim Morgan 4,  David M Markie 22,  Michela Fagiolini 1 2 3,  Amy Swift 16,  Peter S Chines 16,  Carlos E Speck-Martins 23,  Francis S Collins 16 24,  Ethylin Wang Jabs 11 13,  Carsten G Bönnemann 17 18,  Eric N Olson 6,  Moebius Syndrome Research Consortium,  John C Carey 25,  Stephen P Robertson 4,  Irini Manoli 16,  Elizabeth C Engle 1 2 3 8 10 12 26 27
Affiliations

Affiliations

  • 1 Department of Neurology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 2 F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 3 Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 4 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • 5 Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
  • 6 Department of Molecular Biology and Neuroscience, and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 USA.
  • 7 Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 8 Medical Genetics Training Program, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 9 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 10 Broad Institute of M.I.T. and Harvard, Cambridge, Massachusetts 02142, USA.
  • 11 McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
  • 12 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
  • 13 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
  • 14 Department of Radiology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 15 Department of Radiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 16 Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1477, USA.
  • 17 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1477, USA.
  • 18 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1477, USA.
  • 19 Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
  • 20 Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine, Hanover, New Hampshire 03755-1404, USA.
  • 21 Genetic Health Services New Zealand, Auckland City Hospital, Auckland 1142, New Zealand.
  • 22 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • 23 SARAH Network of Rehabilitation Hospitals, Brasilia 70335-901, Brazil.
  • 24 Office of the Director, National Institutes of Health, Bethesda, Maryland 20892-1477, USA.
  • 25 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
  • 26 Department Ophthalmology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 27 Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 28681861 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.

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