3 of the 4 documented patients with stiff patient syndrome have mutations at the interface of actin and tropomyosin and therefore could affect the equilibrium of the Ca2+-dependent switch of muscle. ACTA1 gene (skeletal actin) K326N was previously reported, and we recently found stiff patients with ΔE218 and ΔE224 mutations in the TPM3 gene (Tpm3.12 protein). The atomic resolution structure of tropomyosin bound to actin in the ‘switched off’ state shows that tropomyosin makes contact with actin at only two points, one of which is a cluster of basic amino acids actin K326, K328 and R147.