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

Journal article

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 beta-tropomyosin (beta-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 beta-TM, Arg174Gln TnI, and a TnI truncation mutant (Arg156ter). Thin filaments, reconstituted using actin and WT troponin and beta-TM, activated myosin subfragment-1 ATPase in a calcium-dependent, cooperative manner. Thin filaments containing either a troponin or beta-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 beta-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.

Authors: Robinson, P; Lipscomb, S; Preston, L; Altin, E; Watkins, H

• Publication status: Published
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• Volume: 21
• Issue: 3
• Pages: 896-905
• Publication date: 2007-03-01
• DOI: 10.1096/fj.06-6899com
• EISSN: 1530-6860
• ISSN: 0892-6638
• Language: English
• Keywords: Arginine; Glycine; Amino Acid Substitution; Actins; Troponin T; Muscle Contraction; Arthrogryposis; Muscle, Skeletal; Myosins; Rabbits; Tropomyosin; Animals; Humans; Calcium; Mutation; Troponin I