Davidson, Ann E and Siddiqui, Fazeel M and Lopez, Michael A and Lunt, Peter and Carlson, Heather A and Moore, Brian E and Love, Seth and Born, Donald E and Roper, Helen and Majumdar, Anirban and Jayadev, Suman and Underhill, Hunter R and Smith, Corrine O and von der Hagen, Maja and Hubner, Angela and Jardine, Philip and Merrison, Andria and Curtis, Elizabeth and Cullup, Thomas and Jungbluth, Heinz and Cox, Mary O and Winder, Thomas L and Abdel Salam, Hossam and Li, Jun Z and Moore, Steven A and Dowling, James J (2013) Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies. Brain : a journal of neurology, 136 (Pt 2). pp. 508-21. ISSN 1460-2156. This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDsFull text not available from this repository.
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.
|Additional Information:||This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDs|
|Subjects:||QC-QM General sciences
|Divisions:||Womens and Childrens > Paediatrics|
|Depositing User:||Sophie Rollason|
|Date Deposited:||11 Jun 2014 13:30|
|Last Modified:||11 Jun 2014 13:30|
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