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

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