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The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle

Racca, Alice W., Beck, Anita E., McMillin, Margaret J., Korte, F. Steven, Bamshad, Michael J., Regnier, Michael (2015) The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. Human Molecular Genetics, 24 (12). pp. 3348-3358. ISSN 0964-6906. E-ISSN 1460-2083. (doi:10.1093/hmg/ddv084) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://doi.org/10.1093/hmg/ddv084

Abstract

Distal arthrogryposis is the most common known heritable cause of congenital contractures (e.g. clubfoot) and results from mutations in genes that encode proteins of the contractile complex of skeletal muscle cells. Mutations are most frequently found in MYH3 and are predicted to impair the function of embryonic myosin. We measured the contractile properties of individual skeletal muscle cells and the activation and relaxation kinetics of isolated myofibrils from two adult individuals with an R672C substitution in embryonic myosin and distal arthrogryposis syndrome 2A (DA2A) or Freeman-Sheldon syndrome. In R672C-containing muscle cells, we observed reduced specific force, a prolonged time to relaxation and incomplete relaxation (elevated residual force). In R672C-containing muscle myofibrils, the initial, slower phase of relaxation had a longer duration and slower rate, and time to complete relaxation was greatly prolonged. These observations can be collectively explained by a small subpopulation of myosin cross-bridges with greatly reduced detachment kinetics, resulting in a slower and less complete deactivation of thin filaments at the end of contractions. These findings have important implications for selecting and testing directed therapeutic options for persons with DA2A and perhaps congenital contractures in general.

Item Type: Article
DOI/Identification number: 10.1093/hmg/ddv084
Subjects: Q Science
Q Science > QP Physiology (Living systems)
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: A.W. Racca
Date Deposited: 11 Jan 2016 14:47 UTC
Last Modified: 29 May 2019 16:52 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/53684 (The current URI for this page, for reference purposes)
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