Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies BRAIN 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., Salam, H. A., Li, J. Z., Moore, S. A., Dowling, J. J. 2013; 136: 508-521

Abstract

The ß-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and ß-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 ß-tropomyosin-related myopathies through the identification of a novel ß-tropomyosin mutation in two clinical contexts not previously associated with ß-tropomyosin. The first clinical phenotype is core-rod myopathy, with a ß-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 ß-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 a-helices of dimeric ß-tropomyosin, a change predicted to alter protein-protein binding between ß-tropomyosin and other molecules and to disturb head-to-tail polymerization of ß-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del ß-tropomyosin in the developing zebrafish. p.K7del ß-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 ß-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel ß-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with ß-tropomyosin and pathogenic data from the first animal model of ß-tropomyosin-related myopathies.

View details for DOI 10.1093/brain/aws344

View details for Web of Science ID 000314995200020

View details for PubMedCentralID PMC3572924