The Sarcomere and Skeletal Muscle Disease

Part I. The Sarcomere 1. The Sarcomere and Sarcomerogenesis...... 1 Elisabeth Ehler and Mathias Gautel Abstract......... 1 Introduction.......... 1 Insights in Sarcomere Assembly from Cell Culture Studies.......... 3 Associated Proteins, Scaffolds and Cofactors........... 5 Sarcomere Assembly in vivo: What Is Different?............ 9 Lessons from Knockout Animals.......... 10 Future Perspectives.......... 11 Part II. Thin Filament Diseases 2. Skeletal Muscle Alpha-Actin Diseases........ 15 Kathryn N. North and Nigel G. Laing Abstract.......... 15 Introduction........... 15 Clinical Features........... 16 Histopathology........... 18 Genetics........... 18 Molecular Modelling of the Effect of ACTA1 Mutations........... 22 What Do the Patients Tell Us about the Pathophysiology of ACTA1 Diseases?.......... 22 What Do the Patients Tell Us about Possible Treatments? -Lessons from the Clinic in the Development of Therapies.......... 24 Future Directions........... 25 3. Nebulin-A Giant Chameleon......... 28 Katarina Pelin and Carina Wallgren-Pettersson Abstract........ 28 Introduction.......... 28 The Nebulin Protein.......... 28 The Nebulin Gene........... 30 Mutations in the Nebulin Gene........... 32 DNA-Diagnostic Dilemma........... 33 Autosomal Recessive Nemaline (rod) Myopathy.......... 33 Autosomal Recessive Distal Nebulin Myopathy.......... 35 Conclusions (Future Applications, New Research, Anticipated Developments)......... 36 4. Skeletal Muscle Disease Due to Mutations in Tropomyosin, Troponin and Cofilin........ 40 Nigel F. Clarke Abstract......... 40 Introduction......... 40 Mutations in Tropomyosin Associated with SkeletalMuscle Disease.......... 41 Concluding Remarks and Future Directions.......... 50 5. Investigat ions into the Pathobiology of Thin-Filament Myopathies......... 55 Biljana Ilkovski Abstract.......... 55 Introduction........... 55 Actin.......... 55 Tropomyosin........... 60 Nebulin.......... 61 Troponin.......... 62 a-Actinin 2......... 62 Cofilin.......... 63 Conclusions and Future Directions............ 63 6. Mouse Models for Thin Filament Disease......... 66 Mai-Anh T. Nguyen and Edna C. Hardeman Abstract............ 66 Introduction........... 66 Nemaline Myopathy........... 68 Skeletal Muscle Alpha Actin (ACTA1) Diseases........... 68 Nebulin (NEB) Diseases........... 68 Tropomyosin Diseases............ 69 Troponin and Cofilin Diseases............ 69 Tropomyosin Mouse Model for Nemaline Myopathy......... 69 Nebulin Null Mouse Models........... 71 a-Skeletal Actin Mouse Models for Nemaline and Other Myopathies.......... 71 Mouse Models for Cardiomyopathies.......... 72 Therapies for NM-Insights from Mouse Models.......... 72 Future Directions........... 74 Part III. Thick Filament Diseases 7. Thick Filament Diseases......... 78 Anders Oldfors and Phillipa J. Lamont Abstract.......... 78 Introduction........... 78 Myopathies Associated with Myh2 Mutations............ 79 Myopathies Associated with Myh3 Mutations........... 82 Skeletal Myopathies Associated with Myh7 Mutations........... 83 Myopathies Associated with Myh8 Mutations............ 88 Future Perspectives, New Applications and Anticipated Developments............ 90 8. Acute Quadriplegic Myopathy: An Acquired 'Myosinopat hy'.......... 92 Lars Larsson Abstract..........