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Mutations in fast skeletal troponin I, troponin T, and ß-tropomyosin that cause distal arthrogryposis all increase contractile function

Paul Robinson^*, Simon Lipscomb, Laura C. Preston^*,, Elissa Altin^*, Hugh Watkins^*, Christopher C. Ashley and Charles S. Redwood^*,1

Departments of
^* Cardiovascular Medicine and

Physiology, University of Oxford, Oxford, UK

¹Correspondence: Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre of Human Genetics, Oxford OX3 7BN, UK. E-mail: credwood{at}well.ox.ac.uk

Distal arthrogryposes (DAs) are a group of disorders characterized by congenital contractures of distal limbs without overt neurological or muscle disease. Unexpectedly, mutations in genes encoding the fast skeletal muscle regulatory proteins troponin T (TnT), troponin I (TnI), and ß-tropomyosin (ß-TM) have been shown to cause autosomal dominant DA. We tested how these mutations affect contractile function by comparing wild-type (WT) and mutant proteins in actomyosin ATPase assays and in troponin-replaced rabbit psoas fibers. We have analyzed all four reported mutants: Arg63His TnT, Arg91Gly ß-TM, Arg174Gln TnI, and a TnI truncation mutant (Arg156ter). Thin filaments, reconstituted using actin and WT troponin and ß-TM, activated myosin subfragment-1 ATPase in a calcium-dependent, cooperative manner. Thin filaments containing either a troponin or ß-TM DA mutant produced significantly enhanced ATPase rates at all calcium concentrations without alternating calcium-sensitivity or cooperativity. In troponin-exchanged skinned fibers, each mutant caused a significant increase in Ca²⁺ sensitivity, and Arg156ter TnI generated significantly higher maximum force. Arg91Gly ß-TM was found to have a lower actin affinity than WT and form a less stable coiled coil. We propose the mutations cause increased contractility of developing fast-twitch skeletal muscles, thus causing muscle contractures and the development of the observed limb deformities.—Robinson, P., Lipscomb, S., Preston, L. C., Altin, E., Watkins, H., Ashley, C. C., Redwood, C. S. Mutations in fast skeletal troponin I, troponin T, and ß-tropomyosin that cause distal arthrogryposis all increase contractile function.

Key Words: contractility • muscle disease

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