Troponinology: Skeletal muscle troponin in congenital myopathies

The sarcomere is an intricate and well-tuned machinery generating force contraction after contraction, performing like a well-made Swiss watch. The smallest defect to a cog will cause a watch to go out of sync. The smallest defect in a protein could cause sarcomere dysfunction. In this thesis, several of these small defects are described. These defects are caused by gene variants, resulting in a different protein compared to a healthy protein. Most of the variants described here are point mutations which could cause structural and functional changes in the protein. The aim of this thesis was to study the effect of these gene variants on sarcomere structure and function to determine the pathomechanism behind the resulting myopathies. In chapter 5 & 6 we establish the pathogenicity of mutations in TNNC2 and TNNI1 and suggest possible therapeutic strategies. Chapter 7 describes the pathophysiology of a mutation in MYH7. In chapter 8 we describe an experimental setup enabling the investigation of sarcomere mechanics in myofibrils and in chapter 9 we utilise this technique to study MARP1 effects in the sarcomere.1