The Sarcomere and Skeletal Muscle Disease (eBook)

Nigel G. Laing, PhD, is currently a Professorial Fellow in the Centre for Medical Research at the University of Western Australia, within the Western Australian Institute for Medical Research at the QEII Medical Centre in Western Australia and a Senior Medical Scientist in the Neurogenetic Laboratory at Royal Perth Hospital, Western Australia. He is however originally Scottish, doing his undergraduate studies, Honours in Pharmacology (1976), PhD in Physiology (1979), at the University of Edinburgh. His thesis was on the effects of bungarotoxin paralysis on motor neuron death in the developing chick embryo and was supervised by Martin Prestige. He had a one-year post-doc with Professor Jan Jansen in the Department of Physiology at the University of Oslo in 1980. After that he moved to the Department of Pathology at the University of Western Australia for another post-doc position with Alan Lamb from 1981-1987. In 1987-1988 he re-trained in molecular genetics with Professor Teepu Siddique in Professor Allen Roses’ laboratory at Duke University, North Carolina, returning to Western Australia in July 1988 to develop both research and diagnostic molecular neurogenetics laboratories under Professor Byron Kakulas. The research laboratory (first in the Australian Neuromuscular Research Institute and subsequently in the Western Australian Institute for Medical Research), has played a role in showing SOD1 was a gene for familial amyotrophic lateral sclerosis. It also identified mutation of slow a-tropomyosin as the first known cause of the congenital myopathy nemaline myopathy, and mutations in skeletal muscle a-actin as a significant cause of congenital myopathies (especially severe congenital myopathies) and that certain specific mutations in the tail of slow skeletal/ß-cardiac myosin are associated with an early onset form of distal myopathy, now known as Laing distal myopathy. The Neurogenetic Laboratory at Royal Perth Hospital provides a state-wide molecular diagnostic service for neurological disorders, an Australasia-wide service for some of these disorders and is a world reference centre for the diagnosis of skeletal muscle a-actin and slow a-tropomyosin disorders.

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..........