C.P.15 K7del is a recurrent TPM2 nemaline myopathy mutation associated with joint contractures and increased calcium sensitivity

Abstract

The TPM2 gene encodes beta-tropomyosin (βTm). A range of TPM2 mutations have been associated with several congenital myopathies and distal arthrogryposis. We report a novel dominant TPM2 mutation, K7del, in five unrelated families (de novo occurrence was likely in four families and could be confirmed in two). This mutation removes a highly conserved lysine residue within the N-terminal region that mediates βTm head-to-tail polymerisation. Patients had postnatal large joint contractures and little skeletal muscle weakness until adulthood. Muscle histology showed nemaline bodies and core-like areas, and there was marked fatty infiltration of lower limb muscles by mid-adulthood on muscle MRI. We performed a wide range of studies to investigate the causes of muscle dysfunction. 2D-gel electrophoresis on patient muscle and primary patient cultured myotubes suggested that mutant protein incorporates poorly into sarcomeres and most resides in nemaline rods. Recombinant K7del protein showed a reduced ability to polymerise into long filaments and reduced actin affinity but bound to thin filaments when mixed with wild-type βTm and caused an in myofibrillar calcium sensitivity. Single dissected patient muscle fibres also showed increased calcium sensitivity of force generation. In summary, K7del is a recurrent TPM2 mutation that causes mild nemaline myopathy with core-like features and postnatal contractures. Mutant K7del protein incorporates poorly into sarcomeres likely due to abnormal head-to-tail polymerisation and reduced actin affinity. Joint contractures may arise from muscle hypercontraction due to increased 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.