Mutations in the TPM2 gene, which encodes β-
tropomyosin, are an established cause of several congenital skeletal
myopathies and distal
arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with
nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint
contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved
lysine residue near the N-terminus of β-
tropomyosin, which is predicted to disrupt head-to-tail polymerization of
tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that
mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament
calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild
nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of
tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the
troponin/
tropomyosin-dependent
calcium switch of muscle. Joint
contractures may stem from chronic muscle hypercontraction due to increased myofibrillar
calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from
therapies that reduce skeletal muscle
calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity.