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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 Jungbluth , Mary O. Cox , Thomas L. Winder , Hossam Abdel Salam , Jun Z. Li , Steven A. Moore , James J. Dowling
DOI: http://dx.doi.org/10.1093/brain/aws344 508-521 First published online: 14 February 2013

Summary

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.

  • nemaline
  • myopathies
  • muscle and nerve pathology
  • mutation
  • neuromuscular disorders
  • Abbreviations
    GFP
    green fluorescent protein
    TPM2
    β-Tropomyosin
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