Molecular Genetics of Myopathies Caused by β‐Tropomyosin Mutations

Abstract

Abstract Mutations in the gene encoding β‐tropomyosin, TPM2 , cause clinically and histologically overlapping congenital myopathies such as nemaline myopathy, cap myopathy and core‐rod myopathy, and often also a fibre size disproportion between type 1 and type 2 muscle fibres. In addition, TPM2 mutations can cause distal arthrogryposis and Escobar syndrome, or unspecific myopathies with various combinations of clinical and histological features. The vast majority of the TPM2 mutations are dominant, either de novo or familial. Missense mutations and in‐frame deletions or insertions of single amino acids are the most common types of mutation. Three dominant donor splice site mutations have also been described, predicted to cause exon skipping and subsequent loss of 42 amino acids. Only one recessive mutation has been identified in TPM2 , that is, a nonsense mutation causing nemaline myopathy with Escobar syndrome. Of the 30 different TPM2 mutations identified to date, six are gain‐of‐function mutations causing increased muscle contractility. Key Concepts: Dominant mutations in the TPM2 gene cause a variety of congenital myopathies and distal arthrogryposis. Recessive mutations in TPM2 are rare. Tropomyosin mutations alter actin‐tropomyosin interactions, tropomyosin dimer formation and muscle contraction. Gain‐of‐function mutations cause increased muscle contractility. Hypercontractile molecular phenotypes result in distal arthrogryposis and congenital myopathies with contractures.