D.P.8 Expanding the clinical and genetic phenotype of TPM2-related myopathies

Abstract

The beta-tropomyosin gene (TPM2) encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin–myosin interactions, and TPM2 mutations have been associated with nemaline myopathy, cap myopathy and distal arthrogryposis. In this study, we expand the allelic spectrum of TPM2-related myopathies through the identification of a novel TPM2 mutation in a family with core-rod myopathy and in a family with trismus-pseudocamptodactyly. In addition, we describe the first animal models of TPM2 related myopathies, and use these models to compare and contrast pathogenic mechanisms related to distinct TPM2 mutations. The first new phenotype is core-rod myopathy, with the TPM2 mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy. The second phenotype is trismus-pseudocamptodactyly syndrome (previously associated exclusively with MYH8 mutations), with mutation identified by candidate gene analysis based on the observation of nemaline rods on muscle biopsy. In both cases, the mutation identified is a novel three base pair in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the 7th amino acid position. Conceptual modeling of this mutation predicts that it disrupts the N-terminal homodimeric alpha helix of TPM2, a change that likely alters protein–protein binding between TPM2 and other molecules. We are now utilizing the zebrafish model system to generate a transgenic model of both this TPM2 mutation as well as a recurrent TPM2 mutation (E139del) associated with cap myopathy. These models are used to determine the underlying pathomechanisms associated with different TPM2 mutations via direct comparisons as well as through comparison with existing nemaline myopathy and core myopathy zebrafish models. In all, we describe a novel TPM2 mutation, two clinical-histopathologic phenotypes not previously associated with TPM2, and the first animal models of TPM2 related myopathies.