TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype

Sandra Donkervoort, Maria Papadaki, Josine M. De Winter, Matthew B. Neu, Janbernd Kirschner, Véronique Bolduc, Michele L. Yang, Melissa A. Gibbons, Ying Hu, Jahannaz Dastgir, Meganne E. Leach, Anne Rutkowski, A. Reghan Foley, Marcus Krüger, Eric P. Wartchow, Elyshia McNamara, Royston Ong, Kristen J. Nowak, Nigel G. Laing, Nigel F. ClarkeCoen A.C. Ottenheijm, Steven B. Marston, Carsten G. Bönnemann

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)985-994
Number of pages10
JournalAnnals of Neurology
Volume78
Issue number6
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint

Dive into the research topics of 'TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype'. Together they form a unique fingerprint.

Cite this