The Sarcomere and Skeletal Muscle Disease

ISBN-13: 9780387848464 / Angielski / Twarda / 2008 / 228 str.

Nigel G. Laing; Nigel G. Laing

Opis

The gene, and its protein product, in a serious inherited muscle disease was first identified in the case of Duchenne muscular dystrophy some twenty years ago. Dystrophin turned out to be a sarcolemmal protein. This was somewhat of a surprise because many had harboured the view up until then that most muscle diseases, if not all, might be due to defects in the sarcomere itself. After all this was the site of muscle contraction. However many other muscular dystrophies have subsequently been shown to be due to defects in various other sarcolemma-associated proteins.¹ The structure of the sarcomere itself has been studied and known for many years.² But only in more recent times has the role of its structural and contractile proteins been detailed in specific muscle diseases. The cytoskeleton is held together by filamentous proteins, such as a-actinin and desmin, and the microtubular protein tubulin. Other proteins are nebulin and telethonin and the elastic element titin. Finally there are the contractile proteins troponin, tropomyosin, actin and myosin. Here experts in the field describe a variety of diseases associated with defects in these sarcomeric proteins often first suspected because of a pronounced accumulation of the relevant protein in the muscle tissue. Recently a few, relatively rare dystrophies themselves have also been shown to be associated with defects in sarcomeric proteins, for example, myotilin in LGMD1A, telethonin in LGMD2G, and titin in LGMD2J. The latter is of particular interest in the present context. Whereas homozygous mutation of the titin gene result in the autosomal recessive, severe, early onset 2J form of limb-girdle muscular dystrophy, heterozygosity for the same and other dominant mutations results in a mild, late onset form of distal (tibial) myopathy.^3,4 Furthermore myotilin mutations have now been demonstrated in myofibrillar myopathy, or desmin-related myopathy, as well as in LGMD1A.⁵ These observations and several other examples in the text raise fundamental questions: how do we explain the very different clinical phenotypes which can result from different mutations in the same gene, and occasionally in different members of the same family with the same mutation? This problem is not unique to the sarcomeric diseases. It is also well exemplified in the case of mutations of the LMNA gene resulting in multiple laminopathies, defects in nuclear membrane proteins, a problem which has been recognised for some time.⁶ Further detailed analysis of specific mutations in these disorders may provide some answers. But it is also possible that studying associations with single nucleotide polymorphisms or copy number variants^7-10 may be helpful though so far most of this research has centred more on commoner multifactorial conditions. These seem to be unexplored territories in regard to genetic forms of muscle disease. Furthermore acute quadriplegic myopathy, due to a preferential loss of myosin and myosin-associated thick filament proteins, is acquired and not genetic. It is also perhaps possible that certain common pathogens could affect disease presentation via their interaction with, for example, actin filaments and the induced filament rearrangements.¹¹ But again this is a field which has so far not been explored. The results of the studies presented in this volume now pave the way for much future research into the pathogenesis of this group of fascinating conditions, leading one day to their treatment. References: 1. Winder SJ, ed. Molecular Mechanisms of Muscular Dystrophies. Austin: Landes Bioscience, 2006. 2. Hanson J, Huxley HE. Structural basis of cross striations in muscle. Nature 1953; 172:530-533. 3. Udd B, Kaarianen H, Somer H. Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 1991; 14:1050-1058. 4. Hackman P, Vihola A, Haravuori H et al. Tibial muscular dystrophy is a titinopathy caused by mutations in TT N, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 2002; 71:492-500. 5. Selcen D, Engel AG. Mutations in myotilin cause myofibrillar myopathy. Neurology 2004; 62:1363-1371. 6. Emery AEH. The muscular dystrophies. Lancet 2002; 359:687-695 (see OMIM 150330). 7. Christensen K, Murray JC . What genome-wide association studies can do for medicine. New Engl J Med 2007; 356:1094-1097. 8. Redon R, Ishikawa S, Fitch KR et al. Global variation in copy number in the human genome. Nature 2006; 444:444-454. 9. Lock DP, Sharp AJ, McCarroll SA et al. Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome. Am J Hum Genet 2006; 79:275-290. 10. Stranger BE, Forrest MS, Dunning M et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 2007; 315:848-853. 11. Rottner K, Lommel S, Wehland J, Stradal TEB. Pathogen-induced actin filament rearrangement in infectious diseases. J Pathol 2004; 204:396-406.

Spis treści

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..........

O autorze

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.