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

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. Webb, Caroline D. Robson, Long Cheng, Carol Van Ryzin, Andres Ramirez-Martinez, Payam Mohassel, Mark Leppert, Mary Beth Scholand, Christopher Grunseich, Carlos R. Ferreira, Tyler Hartman, Ian M. Hayes, Tim Morgan, David M. Markie, Michela Fagiolini, Amy Swift, Peter S. Chines, Carlos E. Speck-Martins, Francis S. Collins, Ethylin Wang Jabs, Carsten G. Bönnemann, Eric N. Olson, John C. Carey (), Stephen P. Robertson, Irini Manoli () and Elizabeth C. Engle ()
Additional contact information
Silvio Alessandro Di Gioia: Boston Children’s Hospital
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
Nicole M. Gilette: Boston Children’s Hospital
Pietro Artoni: Boston Children’s Hospital
Nara Lygia de Macena Sobreira: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Wai-Man Chan: Boston Children’s Hospital
Bryn D. Webb: Icahn School of Medicine at Mount Sinai
Caroline D. Robson: Boston Children’s Hospital
Long Cheng: Boston Children’s Hospital
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
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
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
Ethylin Wang Jabs: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Carsten G. Bönnemann: Neuromuscular and Neurogenetic Disorders of Childhood Section, 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

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms16077

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