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

Author

Listed:
  • Silvio Alessandro Di Gioia

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School)

  • Samantha Connors

    (Dunedin School of Medicine, University of Otago)

  • Norisada Matsunami

    (University of Utah School of Medicine)

  • Jessica Cannavino

    (and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center)

  • Matthew F. Rose

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Boston Children’s Hospital
    Medical Genetics Training Program, Harvard Medical School)

  • Nicole M. Gilette

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital)

  • Pietro Artoni

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School)

  • Nara Lygia de Macena Sobreira

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine)

  • Wai-Man Chan

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Bryn D. Webb

    (Icahn School of Medicine at Mount Sinai)

  • Caroline D. Robson

    (Boston Children’s Hospital
    Harvard Medical School)

  • Long Cheng

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School)

  • Carol Van Ryzin

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health)

  • Andres Ramirez-Martinez

    (and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center)

  • Payam Mohassel

    (Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
    Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health)

  • Mark Leppert

    (University of Utah School of Medicine)

  • Mary Beth Scholand

    (University of Utah School of Medicine)

  • Christopher Grunseich

    (Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health)

  • Carlos R. Ferreira

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health)

  • Tyler Hartman

    (Dartmouth-Hitchcock Medical Center, Geisel School of Medicine)

  • Ian M. Hayes

    (Genetic Health Services New Zealand, Auckland City Hospital)

  • Tim Morgan

    (Dunedin School of Medicine, University of Otago)

  • David M. Markie

    (Dunedin School of Medicine, University of Otago)

  • Michela Fagiolini

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School)

  • Amy Swift

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health)

  • Peter S. Chines

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health)

  • Carlos E. Speck-Martins

    (SARAH Network of Rehabilitation Hospitals)

  • Francis S. Collins

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health
    Office of the Director, National Institutes of Health)

  • Ethylin Wang Jabs

    (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
    Icahn School of Medicine at Mount Sinai)

  • Carsten G. Bönnemann

    (Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
    Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health)

  • Eric N. Olson

    (and Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center)

  • John C. Carey

    (University of Utah School of Medicine)

  • Stephen P. Robertson

    (Dunedin School of Medicine, University of Otago)

  • Irini Manoli

    (Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health)

  • Elizabeth C. Engle

    (Boston Children’s Hospital
    F.M. Kirby Neurobiology Center, Boston Children’s Hospital
    Harvard Medical School
    Medical Genetics Training Program, Harvard Medical School)

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.

Suggested Citation

  • Silvio Alessandro Di Gioia & Samantha Connors & Norisada Matsunami & Jessica Cannavino & Matthew F. Rose & Nicole M. Gilette & Pietro Artoni & Nara Lygia de Macena Sobreira & Wai-Man Chan & Bryn D. We, 2017. "A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16077
    DOI: 10.1038/ncomms16077
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    Cited by:

    1. Viviane Tran & Sarah Nahlé & Amélie Robert & Inès Desanlis & Ryan Killoran & Sophie Ehresmann & Marie-Pier Thibault & David Barford & Kodi S. Ravichandran & Martin Sauvageau & Matthew J. Smith & Marie, 2022. "Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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