Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies

Ann E Davidson, Fazeel M Siddiqui, Michael A Lopez, Peter Lunt, Heather A Carlson, Brian E Moore, Seth Love, Donald E Born, Helen Roper, Anirban Majumdar, Suman Jayadev, Hunter R Underhill, Corrine O Smith, Maja von der Hagen, Angela Hubner, Philip Jardine, Andria Merrison, Elizabeth Curtis, Thomas Cullup, Heinz JungbluthMary O Cox, Thomas L Winder, Hossam Abdel Salam, Jun Z Li, Steven A Moore, James J Dowling

Research output: Contribution to journalArticle (Academic Journal)peer-review

40 Citations (Scopus)


The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
Original languageEnglish
Pages (from-to)508-21
Number of pages14
Issue numberPt 2
Publication statusPublished - Feb 2013


  • Young Adult
  • Animals
  • Humans
  • Lysine
  • Amino Acid Sequence
  • Child
  • Zebrafish
  • Tropomyosin
  • Muscular Diseases
  • Adult
  • Molecular Sequence Data
  • Middle Aged
  • Adolescent
  • Female
  • Male
  • Sequence Deletion


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