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The congenital myopathies include a wide spectrum of clinically, histologically and genetically variable neuromuscular disorders many of which are caused by mutations in genes for sarcomeric proteins. Some congenital myopathy patients have a hypercontractile phenotype. Recent functional studies demonstrated that  ACTA1  K326N and  TPM2  ΔK7 mutations were associated with hypercontractility that could be explained by increased myofibrillar Ca 2+  sensitivity. A recent structure of the complex of actin and tropomyosin in the relaxed state showed that both these mutations are located in the actin–tropomyosin interface. Tropomyosin is an elongated molecule with a 7-fold repeated motif of around 40 amino acids corresponding to the 7 actin monomers it interacts with. Actin binds to tropomyosin electrostatically at two points, through Asp25 and through a cluster of amino acids that includes Lys326, mutated in the gain-of-function mutation. Asp25 interacts with tropomyosin K6, next to K7 that was mutated in the other gain-of-function mutation. We identified four tropomyosin motifs interacting with Asp25 (K6-K7, K48-K49, R90-R91 and R167-K168) and three E-E/D-K/R motifs interacting with Lys326 (E139, E181 and E218), and we predicted that the known skeletal myopathy mutations ΔK7, ΔK49, R91G, ΔE139, K168E and E181K would cause a gain of function. Tests by an  in vitro  motility assay confirmed that these mutations increased Ca 2+  sensitivity, while mutations not in these motifs (R167H, R244G) decreased Ca 2+  sensitivity. The work reported here explains the molecular mechanism for 6 out of 49 known disease-causing mutations in the  TPM2  and  TPM3  genes, derived from structural data of the actin–tropomyosin interface.

Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients