Nemaline myopathy with stiffness and hypertonia associated with an
            <i>ACTA1</i>
            mutation

Jain, Rakesh K.; Jayawant, Sandeep; Squier, Waney; Muntoni, F.; Sewry, Caroline A.; Manzur, Adnan; Quinlivan, R.; Lillis, S.; Jungbluth, Heinz; Sparrow, John C.; Ravenscroft, Gianina; Nowak, Kristen J.; Memo, Massimiliano; Marston, Steven B.; Laing, Nigel G.

doi:10.1212/wnl.0b013e31824e8ebe

Cited by 42 publications

(33 citation statements)

References 6 publications

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“…Additionally, a specific de novo mutation in ACTA1 was found in a newborn with congenital episodic stiffness, hypertrophic muscles and nemaline rod muscle pathology. 14 Our report is the first to demonstrate specific TPM3 deletions as the cause of a novel phenotypic manifestation of marked and generalized congenital muscle stiffness. This phenotype is notable for an absence of muscle weakness in combination with muscle stiffness, so severe that it can result in early ventilatory failure, likely due to an inability of respiratory muscle relaxation, as evidenced by the high inspiratory pressures required during mechanical ventilation in P2.…”

Section: Discussionmentioning

confidence: 62%

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TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Donkervoort

Papadaki

Winter

et al. 2015

Annals of Neurology

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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 case. 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 (IVMA) 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 with 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 This data indicates that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca2+ sensitivity of the troponin-tropomyosin complex, resulting in abnormally active interaction of 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.

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Section: Discussionmentioning

confidence: 62%

“…This study expands the clinical, phenotypic, and pathophysiological spectrum of TPM3 mutations, which now join a specific ACTA1 mutation as well as recessive αβ-crystallin ( CRYAB ) mutations as a myogenic cause for significant neonatal muscle rigidity. 14,15 …”

Section: Introductionmentioning

confidence: 99%

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Donkervoort

Papadaki

Winter

et al. 2015

Annals of Neurology

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“…Tropomyosin was rotated by 180° and shifted to the right to allow a better view of the F-actin–tropomyosin interface. Difference maps of the glutardialdehyde–bare F-actin and the tropomyosin–bare F-actin map are shown on the F-actin surface at pH 7.5 (left) and pH 4.0 (middle), respectively 15,65 .…”

Section: Extended Datamentioning

confidence: 99%

Structure of the F-actin–tropomyosin complex

Ecken

Müller

Lehman

et al. 2014

Nature

335

400

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Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss1, familial thoracic aortic aneurysms and dissections2, and multiple variations of myopathies3. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin4,5. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin6. Although crystal structures for monomeric actin (G-actin) are available7, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 ångstroms in complex with tropomyosin at a resolution of 6.5ångstroms, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify the density corresponding to ADP and Mg2+ and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin–tropomyosin with its position in our previously determined actin–tropomyosin–myosin structure8 reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.

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“…For instance, M531R mutants in the motor domain of the human β/slow-cardiac myosin molecule have been shown to be stronger motors and have been suggested to interrupt myosin head putative interactions with other proteins (eg, myosin-binding protein C) resulting in hyperdynamic heart 18. In contrast to congenital cardiomyopathies where a vast number of mutations have hypercontractile consequences, most of skeletal myopathies-related mutations induce hypocontractility and overall weakness,17 19–21 with only a few exceptions contributing to muscle stiffness and/or hypertonia 22 23…”

Section: Hypercontractile or Hypocontractile Myofilamentsmentioning

confidence: 99%

Novel myosin-based therapies for congenital cardiac and skeletal myopathies

Ochala

Sun

2016

J Med Genet

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The dysfunction in a number of inherited cardiac and skeletal myopathies is primarily due to an altered ability of myofilaments to generate force and motion. Despite this crucial knowledge, there are, currently, no effective therapeutic interventions for these diseases. In this short review, we discuss recent findings giving strong evidence that genetically or pharmacologically modulating one of the myofilament proteins, myosin, could alleviate the muscle pathology. This should constitute a research and clinical priority.

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Nemaline myopathy with stiffness and hypertonia associated with an ACTA1 mutation

Cited by 42 publications

References 6 publications

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Structure of the F-actin–tropomyosin complex

Novel myosin-based therapies for congenital cardiac and skeletal myopathies

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