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Sarcomere structure and mechanics in nemaline myopathy: A developing story
Available online at www.sciencedirect.com
ScienceDirect Neuromuscular Disorders 26 (2016) S88–S212 www.elsevier.com/locate/nmd
Abstracts 2016
STRUCTURAL MYOPATHIES AND DISEASES OF THE SARCOMERE S.I.1 Sarcomere structure and mechanics in nemaline myopathy: A developing story C. Ottenheijm VU University medical center, Amsterdam, Netherlands Causes of many myopathies remain unresolved and successful treatment strategies are scarce. A prime example of an unresolved, but life-threatening muscle disease is nemaline myopathy. In muscle cells, the contractile machinery is arranged into sarcomeres, a system of interdigitating thin and thick filaments. Where the thick filament is mainly composed of myosin, the thin filament is composed of an actin backbone decorated with regulatory proteins, such as troponin, tropomyosin and the giant protein nebulin. It is this thin filament that is implicated in nemaline myopathy. Mutations in ten genes have been indicated to play a role, all genes encoding proteins that are either components of the thin filament or are thought to contribute to stability or turnover of thin filament proteins. It is therefore, that nemaline myopathy is considered a ‘thin filament myopathy’. These mutations in thin filament proteins, together with the crucial role of the thin filament in muscle function, raise the question: is the functioning of the thin filament affected in nemaline myopathy, and if so, how? Only in recent years this question has been addressed, and many important ones have yet to be answered. Understanding the genotype–phenotype correlations in nemaline myopathy is important, as it allows for the development of genotype-targeted treatment strategies. http://dx.doi.org/10.1016/j.nmd.2016.06.013
S.I.2 Sarcomeric signalling proteins: Hubs for mechanosensation and hotspots for inherited myopathies M. Gautel, M. Rees, R. Nikoopour, A. Fukuzawa, F. Fraternali, A. Laddach, S. Pernigo, M. Holt, R. Steiner King’s College London BHF Centre for Research Excellence, London, UK The contractile units of striated muscle, the sarcomeres, owe their remarkably regular assembly to the presence of unusually large proteins that combine mechanical, architectural and signalling functions. Titin is the largest single polypeptide protein, linking myofilaments from Z-disc to M-band. It is composed of many Ig and Fn3 type domains and a single MLCK-like kinase domain. The giant size and modular structure of titin mediate multiple functions, from sarcomerogenesis to mechanics, maintenance and adaptation of the sarcomere. At the M-band, titin forms a ternary complex with obscurin/ obsl1 and myomesin that is crucial for the function of the M-band as a mechanical link of myosin filaments. Obscurin, a giant protein up to 800 kDa, is expressed in isoforms containing GEF domains or protein kinase domains. http://dx.doi.org/10.1016/j.nmd.2016.06.015
The giant scaffolds titin and obscurin thus both combine architectural and signalling functions, which are modulated by mechanical stresses on the muscle cytoskeleton. Titin is emerging as a major disease gene in hereditary myopathies, with the titin M-band region being one of the hotspots of diseaserelated mutations. A growing number of disruptive recessive or dominant missense mutations are being linked to a rapidly expanding spectrum of titinopathies, from early-onset paediatric disease to adult onset dilated and hypertrophic cardiomyopathies that disrupt the mechanosignalling hubs formed by titin and obscurin. Correctly classifying pathogenic variants, especially recessive ones that can also be present in control populations, emerges as a major challenge. Harnessing fundamental research in sarcomeric proteins will be increasingly important to improve diagnostic fidelity in an evidence-based way. http://dx.doi.org/10.1016/j.nmd.2016.06.014
S.I.3 Titin-related myopathies: An emerging and growing group of striated muscle diseases A. Ferreiro Pitié-Salpêtrière Hospital, Université Paris Diderot/CNRS & Institute of Myology, Paris, France The 364 exon TTN gene encodes the sarcomere protein titin, which is the largest protein known. Due to its giant size and complexity, titin plays key developmental, mechanical, structural and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was technically impossible due to its massive size. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. Lately, due to the widespread use of NGS, TTN is emerging as a major gene in human inherited disease. More than one hundred disease-causing TTN mutations have been reported in patients with at least 11 different conditions, including purely skeletal muscle phenotypes, isolated cardiomyopathies or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. This talk aims to discuss the growing spectrum of phenotypes associated with TTN (with particular emphasis on skeletal myopathies), the distribution and molecular mechanisms of the TTN mutations reported, their transmission pattern and phenotype–genotype correlations and the challenges in designing effective screening, annotation and functional interpretation tools for the plethora of current and future TTN variants. http://dx.doi.org/10.1016/j.nmd.2016.06.015
ScienceDirect Neuromuscular Disorders 26 (2016) S88–S212 www.elsevier.com/locate/nmd
Abstracts 2016
STRUCTURAL MYOPATHIES AND DISEASES OF THE SARCOMERE S.I.1 Sarcomere structure and mechanics in nemaline myopathy: A developing story C. Ottenheijm VU University medical center, Amsterdam, Netherlands Causes of many myopathies remain unresolved and successful treatment strategies are scarce. A prime example of an unresolved, but life-threatening muscle disease is nemaline myopathy. In muscle cells, the contractile machinery is arranged into sarcomeres, a system of interdigitating thin and thick filaments. Where the thick filament is mainly composed of myosin, the thin filament is composed of an actin backbone decorated with regulatory proteins, such as troponin, tropomyosin and the giant protein nebulin. It is this thin filament that is implicated in nemaline myopathy. Mutations in ten genes have been indicated to play a role, all genes encoding proteins that are either components of the thin filament or are thought to contribute to stability or turnover of thin filament proteins. It is therefore, that nemaline myopathy is considered a ‘thin filament myopathy’. These mutations in thin filament proteins, together with the crucial role of the thin filament in muscle function, raise the question: is the functioning of the thin filament affected in nemaline myopathy, and if so, how? Only in recent years this question has been addressed, and many important ones have yet to be answered. Understanding the genotype–phenotype correlations in nemaline myopathy is important, as it allows for the development of genotype-targeted treatment strategies. http://dx.doi.org/10.1016/j.nmd.2016.06.013
S.I.2 Sarcomeric signalling proteins: Hubs for mechanosensation and hotspots for inherited myopathies M. Gautel, M. Rees, R. Nikoopour, A. Fukuzawa, F. Fraternali, A. Laddach, S. Pernigo, M. Holt, R. Steiner King’s College London BHF Centre for Research Excellence, London, UK The contractile units of striated muscle, the sarcomeres, owe their remarkably regular assembly to the presence of unusually large proteins that combine mechanical, architectural and signalling functions. Titin is the largest single polypeptide protein, linking myofilaments from Z-disc to M-band. It is composed of many Ig and Fn3 type domains and a single MLCK-like kinase domain. The giant size and modular structure of titin mediate multiple functions, from sarcomerogenesis to mechanics, maintenance and adaptation of the sarcomere. At the M-band, titin forms a ternary complex with obscurin/ obsl1 and myomesin that is crucial for the function of the M-band as a mechanical link of myosin filaments. Obscurin, a giant protein up to 800 kDa, is expressed in isoforms containing GEF domains or protein kinase domains. http://dx.doi.org/10.1016/j.nmd.2016.06.015
The giant scaffolds titin and obscurin thus both combine architectural and signalling functions, which are modulated by mechanical stresses on the muscle cytoskeleton. Titin is emerging as a major disease gene in hereditary myopathies, with the titin M-band region being one of the hotspots of diseaserelated mutations. A growing number of disruptive recessive or dominant missense mutations are being linked to a rapidly expanding spectrum of titinopathies, from early-onset paediatric disease to adult onset dilated and hypertrophic cardiomyopathies that disrupt the mechanosignalling hubs formed by titin and obscurin. Correctly classifying pathogenic variants, especially recessive ones that can also be present in control populations, emerges as a major challenge. Harnessing fundamental research in sarcomeric proteins will be increasingly important to improve diagnostic fidelity in an evidence-based way. http://dx.doi.org/10.1016/j.nmd.2016.06.014
S.I.3 Titin-related myopathies: An emerging and growing group of striated muscle diseases A. Ferreiro Pitié-Salpêtrière Hospital, Université Paris Diderot/CNRS & Institute of Myology, Paris, France The 364 exon TTN gene encodes the sarcomere protein titin, which is the largest protein known. Due to its giant size and complexity, titin plays key developmental, mechanical, structural and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was technically impossible due to its massive size. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. Lately, due to the widespread use of NGS, TTN is emerging as a major gene in human inherited disease. More than one hundred disease-causing TTN mutations have been reported in patients with at least 11 different conditions, including purely skeletal muscle phenotypes, isolated cardiomyopathies or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. This talk aims to discuss the growing spectrum of phenotypes associated with TTN (with particular emphasis on skeletal myopathies), the distribution and molecular mechanisms of the TTN mutations reported, their transmission pattern and phenotype–genotype correlations and the challenges in designing effective screening, annotation and functional interpretation tools for the plethora of current and future TTN variants. http://dx.doi.org/10.1016/j.nmd.2016.06.015