TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype
Sandra Donkervoort MS, CGC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorCorresponding Author
Maria Papadaki BSc
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Address correspondence to Dr Bönnemann, National Institutes of Health, Porter Neuroscience Research Center, 35 Convent Drive, Bldg 35, Room 2A-116, Bethesda, MD 20892-3705. E-mail address: [email protected]Search for more papers by this authorJosine M. de Winter MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorMatthew B. Neu BS
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJanbernd Kirschner MD
Department of Neuropediatrics and Muscle Disorders, University Medical Center Freiburg, Freiburg, Germany
Search for more papers by this authorVéronique Bolduc PhD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMichele L. Yang MD
Section of Child Neurology, Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorMelissa A. Gibbons MS, CGC
University of Colorado Denver School of Medicine, Aurora, CO
Search for more papers by this authorYing Hu MS
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJahannaz Dastgir DO
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMeganne E. Leach MSN, APRN, PPCNP-BC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Children's National Health System, Washington, DC
Search for more papers by this authorAnne Rutkowski MD
Cure CMD, Kaiser Southern California Permanente Medical Group, Olathe, KS
Search for more papers by this authorA. Reghan Foley MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMarcus Krüger MD
Department of General Pediatrics, Adolescent Medicine, and Neonatology, University Medical Center Freiburg, Freiburg, Germany
Search for more papers by this authorEric P. Wartchow BSc
Department of Pathology, Children's Hospital Colorado, Aurora, CO
Search for more papers by this authorElyshia McNamara BS
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorRoyston Ong BSc
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorKristen J. Nowak PhD
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorNigel G. Laing PhD
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorNigel F. Clarke PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
Search for more papers by this authorCoen A. C. Ottenheijm PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorSteven B. Marston MA, DPhil, DSc
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Search for more papers by this authorCorresponding Author
Carsten G. Bönnemann MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Address correspondence to Dr Bönnemann, National Institutes of Health, Porter Neuroscience Research Center, 35 Convent Drive, Bldg 35, Room 2A-116, Bethesda, MD 20892-3705. E-mail address: [email protected]Search for more papers by this authorSandra Donkervoort MS, CGC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorCorresponding Author
Maria Papadaki BSc
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Address correspondence to Dr Bönnemann, National Institutes of Health, Porter Neuroscience Research Center, 35 Convent Drive, Bldg 35, Room 2A-116, Bethesda, MD 20892-3705. E-mail address: [email protected]Search for more papers by this authorJosine M. de Winter MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorMatthew B. Neu BS
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJanbernd Kirschner MD
Department of Neuropediatrics and Muscle Disorders, University Medical Center Freiburg, Freiburg, Germany
Search for more papers by this authorVéronique Bolduc PhD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMichele L. Yang MD
Section of Child Neurology, Department of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO
Search for more papers by this authorMelissa A. Gibbons MS, CGC
University of Colorado Denver School of Medicine, Aurora, CO
Search for more papers by this authorYing Hu MS
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorJahannaz Dastgir DO
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMeganne E. Leach MSN, APRN, PPCNP-BC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Children's National Health System, Washington, DC
Search for more papers by this authorAnne Rutkowski MD
Cure CMD, Kaiser Southern California Permanente Medical Group, Olathe, KS
Search for more papers by this authorA. Reghan Foley MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorMarcus Krüger MD
Department of General Pediatrics, Adolescent Medicine, and Neonatology, University Medical Center Freiburg, Freiburg, Germany
Search for more papers by this authorEric P. Wartchow BSc
Department of Pathology, Children's Hospital Colorado, Aurora, CO
Search for more papers by this authorElyshia McNamara BS
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorRoyston Ong BSc
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorKristen J. Nowak PhD
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorNigel G. Laing PhD
Neuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry, and Health Sciences, University of Western Australia, Crawley, Western Australia, Australia; and Harry Perkins Institute of Medical Research, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia
Search for more papers by this authorNigel F. Clarke PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
Search for more papers by this authorCoen A. C. Ottenheijm PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorSteven B. Marston MA, DPhil, DSc
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Search for more papers by this authorCorresponding Author
Carsten G. Bönnemann MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Address correspondence to Dr Bönnemann, National Institutes of Health, Porter Neuroscience Research Center, 35 Convent Drive, Bldg 35, Room 2A-116, Bethesda, MD 20892-3705. E-mail address: [email protected]Search for more papers by this author*These authors contributed equally.
Abstract
Objective
Mutations in TPM3, encoding Tpm3.12, cause a clinically and histopathologically diverse group of myopathies characterized by muscle weakness. We report two patients with novel de novo Tpm3.12 single glutamic acid deletions at positions ΔE218 and ΔE224, resulting in a significant hypercontractile phenotype with congenital muscle stiffness, rather than weakness, and respiratory failure in one patient.
Methods
The effect of the Tpm3.12 deletions on the contractile properties in dissected patient myofibers was measured. We used quantitative in vitro motility assay to measure Ca2+ sensitivity of thin filaments reconstituted with recombinant Tpm3.12 ΔE218 and ΔE224.
Results
Contractility studies on permeabilized myofibers demonstrated reduced maximal active tension from both patients with increased Ca2+ sensitivity and altered cross-bridge cycling kinetics in ΔE224 fibers. In vitro motility studies showed a two-fold increase in Ca2+ sensitivity of the fraction of filaments motile and the filament sliding velocity concentrations for both mutations.
Interpretation
These data indicate that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca2+ sensitivity of the troponin–tropomyosin complex, resulting in abnormally active interaction of the actin and myosin complex. Both mutations are located in the charged motifs of the actin-binding residues of tropomyosin 3, thus disrupting the electrostatic interactions that facilitate accurate tropomyosin binding with actin necessary to prevent the on-state. The mutations destabilize the off-state and result in excessively sensitized excitation–contraction coupling of the contractile apparatus. This work expands the phenotypic spectrum of TPM3-related disease and provides insights into the pathophysiological mechanisms of the actin–tropomyosin complex. Ann Neurol 2015;78:982–994
Supporting Information
Additional supporting information can be found in the online version of this article.
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