Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies
- Authors
- Davidson, A.E., Siddiqui, F.M., Lopez, M.A., Lunt, P., Carlson, H.A., Moore, B.E., Love, S., Born, D.E., Roper, H., Majumdar, A., Jayadev, S., Underhill, H.R., Smith, C.O., von der Hagen, M., Hubner, A., Jardine, P., Merrison, A., Curtis, E., Cullup, T., Jungbluth, H., Cox, M.O., Winder, T.L., Abdel Salam, H., Li, J.Z., Moore, S.A., and Dowling, J.J.
- ID
- ZDB-PUB-130308-14
- Date
- 2013
- Source
- Brain : a journal of neurology 136(2): 508-521 (Journal)
- Registered Authors
- Dowling, Jim
- Keywords
- none
- MeSH Terms
-
- Adolescent
- Adult
- Amino Acid Sequence
- Animals
- Child
- Female
- Humans
- Lysine/genetics*
- Male
- Middle Aged
- Molecular Sequence Data
- Muscular Diseases/diagnosis*
- Muscular Diseases/genetics*
- Muscular Diseases/pathology
- Sequence Deletion*
- Tropomyosin/chemistry
- Tropomyosin/genetics*
- Young Adult
- Zebrafish
- PubMed
- 23413262 Full text @ Brain
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.