Evidence map›Paper›PMID 26418456›Full record

ArticleAnnals of neurology2015

TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.

S Donkervoort, M Papadaki, J M de Winter, M B Neu, J Kirschner, V Bolduc, M L Yang, M A Gibbons, Y Hu, J Dastgir and 13 more

Open access · bronzeAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed
1.9field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 44 citations in OpenAlex.

  1. Review
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  6. A Novel Variant inInternational journal of molecular sciences · 2023
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  16. Sarcomeric myopathies associated with tremor: new insights and perspectives.Journal of muscle research and cell motility · 2020
    Article
  17. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 9 institutions in 5 countries.

S DonkervoortNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
M Papadaki *National Heart and Lung Institute, Imperial College London, London, UK.
J M de Winter *Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
M B Neu *National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
J KirschnerDepartment of Neuropediatrics and Muscle Disorders, University Medical Center Freiburg, Freiburg, Germany.
V BolducNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
M L YangUniversity of Colorado School of Medicine, Department of Pediatrics and Neurology, Section of Child Neurology, Aurora, CO, USA.
M A GibbonsUniversity of Colorado Denver School of Medicine, Aurora, CO, USA.
Y HuNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
J DastgirNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
M E LeachNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
A RutkowskiKaiser SCPMG, Cure CMD, P.O. Box 701, Olathe, KS 66051, USA.
A R FoleyNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
M KrügerDepartment of General Pediatrics, Adolescent Medicine and Neonatology, University Medical Center Freiburg, Freiburg, Germany.
E P WartchowDepartment of Pathology, Children's Hospital Colorado, Aurora, Colorado, USA.
E McNamaraNeuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia Crawley, WA, Australia.
R OngNeuromuscular Diseases Laboratory, Centre for Medical Research, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia Crawley, WA, Australia.
K J NowakNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
N G LaingCentre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, QEII Medical Centre, Perth, Western Australia, Australia.
N F ClarkeInstitute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia.
Cac OttenheijmDepartment of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
S B MarstonNational Heart and Lung Institute, Imperial College London, London, UK.
C G BönnemannNational Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
National Institutes of Health · USUniversity of Colorado Denver · USAmsterdam UMC Location VUmc · NLHarry Perkins Institute of Medical Research · AUImperial College London · GBQueen Elizabeth II Medical Centre · AUUniversity Medical Center Freiburg · DEKaiser Foundation Hospital · USUniversity of Sydney · AU

Funding

Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8M
British Heart Foundation FS/12/24/29568British Heart Foundation RG/11/20/29266Intramural NIH HHS ZIA NS003129
6 · The paper itself

Abstract

objectiveMutations 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.

methodsThe 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 Ca(2+) sensitivity of thin filaments reconstituted with recombinant Tpm3.12 ΔE218 and ΔE224.

resultsContractility studies on permeabilized myofibers demonstrated reduced maximal active tension from both patients with increased Ca(2+) sensitivity and altered cross-bridge cycling kinetics in ΔE224 fibers. In vitro motility studies showed a two-fold increase in Ca(2+) sensitivity of the fraction of filaments motile and the filament sliding velocity concentrations for both mutations.

interpretationThese data indicate that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca(2+) 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.

Indexed as

Muscle ContractionChild, PreschoolExomeFemaleHumansMaleMuscle Fibers, SkeletalMuscular DiseasesMutationPhenotypeRespiratory InsufficiencySequence DeletionTropomyosinTPM3 protein, humanTropomyosin

Identifiers

PMID26418456
PMCPMC5154623
OpenAlexW2161431707

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.