Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy

Jian Ping Jin, Marco A. Brotto, M. Moazzem Hossain, Qi Quan Huang, Leticia S. Brotto, Thomas M. Nosek, D. Holmes Morton, Thomas O. Crawford

Research output: Contribution to journalArticle

Abstract

A lethal form of nemaline myopathy, named "Amish Nemaline Myopathy" (ANM), is linked to a nonsense mutation at codon Glu180 in the slow skeletal muscle troponin T (TnT) gene. We found that neither the intact nor the truncated slow TnT protein was present in the muscle of patients with ANM. The complete loss of slow TnT is consistent with the observed recessive pattern of inheritance of the disease and indicates a critical role of the COOH-terminal T2 domain in the integration of TnT into myofibrils. Expression of slow and fast isoforms of TnT is fiber-type specific. The lack of slow TnT results in selective atrophy of type 1 fibers. Slow TnT confers a higher Ca2+ sensitivity than does fast TnT in single fiber contractility assays. Despite the lack of slow TnT, individuals with ANM have normal muscle power at birth. The postnatal onset and infantile progression of ANM correspond to a down-regulation of cardiac and embryonic splice variants of fast TnT in normal developing human skeletal muscle, suggesting that the fetal TnT isoforms complement slow TnT. These results lay the foundation for understanding the molecular pathophysiology and the potential targeted therapy of ANM.

Original languageEnglish (US)
Pages (from-to)26159-26165
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number28
DOIs
StatePublished - Jul 11 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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