Imperial College London

ProfessorSteveMarston

Faculty of MedicineNational Heart & Lung Institute

(Non-Clinical) Professor in Cardiovascular Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 2732s.marston Website

 
 
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Location

 

433ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Donkervoort:2015:10.1002/ana.24535,
author = {Donkervoort, S and Papadaki, M and de, Winter JM and Neu, MB and Kirschner, J and Bolduc, V and Yang, ML and Gibbons, MA and Hu, Y and Dastgir, J and Leach, ME and Rutkowski, A and Foley, AR and Krüger, M and Wartchow, EP and McNamara, E and Ong, R and Nowak, KJ and Laing, NG and Clarke, NF and Ottenheijm, CA and Marston, SB and Bönnemann, CG},
doi = {10.1002/ana.24535},
journal = {Annals of Neurology},
pages = {982--994},
title = {TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.},
url = {http://dx.doi.org/10.1002/ana.24535},
volume = {78},
year = {2015}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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 Ca(2+) -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 Ca(2+) sensitivity with 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. INTERPRETATION: This data indicates that Tpm3.12 deletions ΔE218 and ΔE224 result in increased Ca(2+) 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. This article is protected by copyright. All rights reserved.
AU - Donkervoort,S
AU - Papadaki,M
AU - de,Winter JM
AU - Neu,MB
AU - Kirschner,J
AU - Bolduc,V
AU - Yang,ML
AU - Gibbons,MA
AU - Hu,Y
AU - Dastgir,J
AU - Leach,ME
AU - Rutkowski,A
AU - Foley,AR
AU - Krüger,M
AU - Wartchow,EP
AU - McNamara,E
AU - Ong,R
AU - Nowak,KJ
AU - Laing,NG
AU - Clarke,NF
AU - Ottenheijm,CA
AU - Marston,SB
AU - Bönnemann,CG
DO - 10.1002/ana.24535
EP - 994
PY - 2015///
SN - 1531-8249
SP - 982
TI - TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.
T2 - Annals of Neurology
UR - http://dx.doi.org/10.1002/ana.24535
UR - http://hdl.handle.net/10044/1/26724
VL - 78
ER -