The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Kay E. Davies - One of the best experts on this subject based on the ideXlab platform.
-
Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons.
Journal of Cell Science, 2010Co-Authors: William T. Clarke, Karl J. A. Mccullagh, Ben Edwards, Matthew Burgess, Matthew Kemp, Catherine Moorwood, Diane L. Sherman, Kay E. DaviesAbstract:Syncoilin is an atypical type III intermediate filament (IF) protein, which is expressed in muscle and is associated with the dystrophin-associated protein complex. Here, we show that Syncoilin is expressed in both the central and peripheral nervous systems. Isoform Sync1 is dominant in the brain, but isoform Sync2 is dominant in the spinal cord and sciatic nerve. Peripherin is a type III IF protein that has been shown to colocalise and interact with Syncoilin. Our analyses suggest that Syncoilin might function to modulate formation of peripherin filament networks through binding to peripherin isoforms. Peripherin is associated with the disease amyotrophic lateral sclerosis (ALS), thus establishing a link between Syncoilin and ALS. A neuronal analysis of the Syncoilin-null mouse (Sync−/−) revealed a reduced ability in accelerating treadmill and rotarod tests. This phenotype might be attributable to the impaired function of extensor digitorum longus muscle and type IIb fibres caused by a shift from large- to small-calibre motor axons in the ventral root.
-
Syncoilin isoform organization and differential expression in murine striated muscle.
Journal of structural biology, 2008Co-Authors: Matthew Kemp, Ben Edwards, Matthew Burgess, W. Thomas Clarke, George Nicholson, David A.d. Parry, Kay E. DaviesAbstract:Abstract Syncoilin is a 64 kDa intermediate filament (IF) protein expressed in myocytes at the sarcolemma, perinucleus, myotendenous and neuromuscular junctions. Here we present a revised domain projection and structural analysis for the original isoform (sync-1) and introduce two novel Syncoilin isoforms (sync-2 and sync-3) generated by exon splicing. On the basis of consensus identity we propose that Syncoilin be reclassified as a type III IF protein. All three Syncoilin isoforms lack a L1 domain, a significant departure from standard IF rod domain projections that is likely to impact significantly on their biological function. Our analyses indicate that Syncoilin is unlikely to form classical intermediate filament structures by itself, and that the significant difference in C-terminal structure between the three isoforms indicates that they may play divergent roles in myocytes. We show that despite lacking an apparent structural role in striated muscle, Syncoilin isoforms are differentially and strongly upregulated in response to cardiotoxin induced regeneration and denervation induced atrophy in the C57BL/6 mouse, possibly suggesting an atypical role for Syncoilin in muscle.
-
Nuclear Organization in Development and Disease: Novartis Foundation Symposium 264 - Muscular dystrophies related to the cytoskeleton/nuclear envelope.
Novartis Foundation symposium, 2008Co-Authors: Kristen J. Nowak, Ellen Poon, Karl J. A. Mccullagh, Kay E. DaviesAbstract:Mutations in genes encoding proteins expressed in skeletal muscle cause a significant number of human diseases. Neuromuscular diseases are often severely debilitating for affected individuals, frequently leading to a shortened life span. Identifying the cause of these muscle diseases has provided insight not only into disease pathogenesis and muscle dysfunction, but also into the normal function of muscle. In 1987, dystrophin became the first disease-related human gene to be identified by positional cloning. Dystrophin is an integral component of the membrane-attached cytoskeleton of muscle fibres, with mutations in this gene causing Duchenne and Becker muscular dystrophy. One group of proteins known as the dystrophin-associated protein complex (DAPC), is believed to provide a molecular link between the actin cytoskeleton and the extracellular matrix in muscle cells, thereby sustaining sarcolemmal integrity during muscle contraction. Mutations in many members of the DAPC cause a variety of diseases, emphasising the importance of these genes. Another group of important proteins in skeletal muscle is the intermediate filament family, which provides mechanical strength and a supporting framework within the muscle cell. They anchor actin thin filaments through their expression at the Z-disk in sarcomeres, which in turn interact with myosin thick filaments to cause muscle contraction. This chapter will explore the protein components of the DAPC and the intermediate filament complex, highlighting a novel protein, which links the two, Syncoilin. Human diseases and studies of existing animal models caused by mutations in these genes will also be described.
-
analysis of skeletal muscle function in the c57bl6 sv129 Syncoilin knockout mouse
Mammalian Genome, 2008Co-Authors: Karl J. A. Mccullagh, Ben Edwards, Laura C. Giles, Matthew Burgess, Matthew Kemp, Kay E. DaviesAbstract:Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, Syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for Syncoilin and the results of an investigation into the effect of a Syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with Syncoilin showed that ablation of Syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our Syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in Syncoilin-deficient muscle. This study establishes a second viable Syncoilin knockout model and highlights the importance of further investigations to determine the role of Syncoilin in skeletal muscle.
-
Analysis of skeletal muscle function in the C57BL6/SV129 Syncoilin knockout mouse
Mammalian Genome, 2008Co-Authors: Karl J. A. Mccullagh, Ben Edwards, Matthew W. Kemp, Laura C. Giles, Matthew Burgess, Kay E. DaviesAbstract:Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, Syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for Syncoilin and the results of an investigation into the effect of a Syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with Syncoilin showed that ablation of Syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our Syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in Syncoilin-deficient muscle. This study establishes a second viable Syncoilin knockout model and highlights the importance of further investigations to determine the role of Syncoilin in skeletal muscle.
Montse Olive - One of the best experts on this subject based on the ideXlab platform.
-
desmin related myopathy clinical electrophysiological radiological neuropathological and genetic studies
Journal of the Neurological Sciences, 2004Co-Authors: Montse Olive, Lev G Goldfarb, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Juan Antonio Martinezmatos, Francesca Martinez, Josefina Alio, Eva FarreroAbstract:Abstract Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, αB-crystallin and amyloid βA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or αB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
-
Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.
Journal of the neurological sciences, 2004Co-Authors: Montse Olive, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Francesca Martinez, Josefina Alio, Lev Goldfarb, Juan Antonio Martínez-matos, Eva FarreroAbstract:Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
-
Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases
Acta Neuropathologica, 2003Co-Authors: Montse Olive, Denise Paulin, Ayush Dagvadorj, Nyamkhishig Sambuughin, Lev Goldfarb, Bertrand Goudeau, Patrick Vicart, Isidro FerrerAbstract:Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and α-actinin. In the present study, the distribution of synemin was examined using immunohistochemistry in muscle biopsy specimens from patients suffering from myofibrillar myopathy (MM, n =6), dermatomyositis (DM, n =3), inclusion body myositis (IBM, n =5), oculopharyngeal muscular dystrophy (OPD, n =3) and denervation atrophy (DA, n =3), to investigate the possible participation of this protein in the pathogenesis of various muscular diseases. Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the αB-crystallin gene; and no mutations were identified in synemin or Syncoilin genes of three patients. Synemin immunohistochemistry disclosed a faint staining corresponding to the Z-bands in the cytoplasm of control muscle fibres; in contrast, focal aggregates of synemin were seen in patients with MM. Increased synemin immunoreactivity was identified diffusely or in the subsarcolemmal space of scattered fibres in patients with DM, and in vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity was observed in target formations and atrophic fibres of patients with denervating disorders, as well as in atrophic fibres, regardless of their origin, in all patients studied. Synemin co-localised with desmin, as seen on consecutive serial sections immunostained with anti-synemin or anti-desmin antibodies. These observations demonstrate abnormal accumulations containing both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and DA. Considering the important role of synemin as one of intermediate filaments of skeletal and cardiac muscle, its destruction and accumulation in the intracellular debris suggest that synemin may participate in the pathogenesis of these disorders.
Karl J. A. Mccullagh - One of the best experts on this subject based on the ideXlab platform.
-
DOI 10.1007/s00335-008-9120-2 Analysis of skeletal muscle function in the C57BL6/SV129 Syncoilin knockout mouse
2013Co-Authors: Matthew Burgess, Karl J. A. Mccullagh, B. Edwards, Æ Kay, E. Davies, M. Kemp W. ContributedAbstract:Abstract Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, Syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for Syncoilin and the results of an investigation into the effect of a Syncoilin null state on striated muscle function in 6–8week-old mice. An analysis of proteins known to associate with Syncoilin showed that ablation of Syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our Syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility t
-
Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons.
Journal of Cell Science, 2010Co-Authors: William T. Clarke, Karl J. A. Mccullagh, Ben Edwards, Matthew Burgess, Matthew Kemp, Catherine Moorwood, Diane L. Sherman, Kay E. DaviesAbstract:Syncoilin is an atypical type III intermediate filament (IF) protein, which is expressed in muscle and is associated with the dystrophin-associated protein complex. Here, we show that Syncoilin is expressed in both the central and peripheral nervous systems. Isoform Sync1 is dominant in the brain, but isoform Sync2 is dominant in the spinal cord and sciatic nerve. Peripherin is a type III IF protein that has been shown to colocalise and interact with Syncoilin. Our analyses suggest that Syncoilin might function to modulate formation of peripherin filament networks through binding to peripherin isoforms. Peripherin is associated with the disease amyotrophic lateral sclerosis (ALS), thus establishing a link between Syncoilin and ALS. A neuronal analysis of the Syncoilin-null mouse (Sync−/−) revealed a reduced ability in accelerating treadmill and rotarod tests. This phenotype might be attributable to the impaired function of extensor digitorum longus muscle and type IIb fibres caused by a shift from large- to small-calibre motor axons in the ventral root.
-
Nuclear Organization in Development and Disease: Novartis Foundation Symposium 264 - Muscular dystrophies related to the cytoskeleton/nuclear envelope.
Novartis Foundation symposium, 2008Co-Authors: Kristen J. Nowak, Ellen Poon, Karl J. A. Mccullagh, Kay E. DaviesAbstract:Mutations in genes encoding proteins expressed in skeletal muscle cause a significant number of human diseases. Neuromuscular diseases are often severely debilitating for affected individuals, frequently leading to a shortened life span. Identifying the cause of these muscle diseases has provided insight not only into disease pathogenesis and muscle dysfunction, but also into the normal function of muscle. In 1987, dystrophin became the first disease-related human gene to be identified by positional cloning. Dystrophin is an integral component of the membrane-attached cytoskeleton of muscle fibres, with mutations in this gene causing Duchenne and Becker muscular dystrophy. One group of proteins known as the dystrophin-associated protein complex (DAPC), is believed to provide a molecular link between the actin cytoskeleton and the extracellular matrix in muscle cells, thereby sustaining sarcolemmal integrity during muscle contraction. Mutations in many members of the DAPC cause a variety of diseases, emphasising the importance of these genes. Another group of important proteins in skeletal muscle is the intermediate filament family, which provides mechanical strength and a supporting framework within the muscle cell. They anchor actin thin filaments through their expression at the Z-disk in sarcomeres, which in turn interact with myosin thick filaments to cause muscle contraction. This chapter will explore the protein components of the DAPC and the intermediate filament complex, highlighting a novel protein, which links the two, Syncoilin. Human diseases and studies of existing animal models caused by mutations in these genes will also be described.
-
analysis of skeletal muscle function in the c57bl6 sv129 Syncoilin knockout mouse
Mammalian Genome, 2008Co-Authors: Karl J. A. Mccullagh, Ben Edwards, Laura C. Giles, Matthew Burgess, Matthew Kemp, Kay E. DaviesAbstract:Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, Syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for Syncoilin and the results of an investigation into the effect of a Syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with Syncoilin showed that ablation of Syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our Syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in Syncoilin-deficient muscle. This study establishes a second viable Syncoilin knockout model and highlights the importance of further investigations to determine the role of Syncoilin in skeletal muscle.
-
Analysis of skeletal muscle function in the C57BL6/SV129 Syncoilin knockout mouse
Mammalian Genome, 2008Co-Authors: Karl J. A. Mccullagh, Ben Edwards, Matthew W. Kemp, Laura C. Giles, Matthew Burgess, Kay E. DaviesAbstract:Syncoilin is a 64-kDa intermediate filament protein expressed in skeletal muscle and enriched at the perinucleus, sarcolemma, and myotendinous and neuromuscular junctions. Due to its pattern of cellular localization and binding partners, Syncoilin is an ideal candidate to be both an important structural component of myocytes and a potential mediator of inherited myopathies. Here we present a report of a knockout mouse model for Syncoilin and the results of an investigation into the effect of a Syncoilin null state on striated muscle function in 6–8-week-old mice. An analysis of proteins known to associate with Syncoilin showed that ablation of Syncoilin had no effect on absolute expression or spatial localization of desmin or alpha dystrobrevin. Our Syncoilin-null animal exhibited no differences in cardiotoxin-induced muscle regeneration, voluntary wheel running, or enforced treadmill exercise capacity, relative to wild-type controls. Finally, a mechanical investigation of isolated soleus and extensor digitorum longus indicated a potential differential reduction in muscle strength and resilience. We are the first to present data identifying an increased susceptibility to muscle damage in response to an extended forced exercise regime in Syncoilin-deficient muscle. This study establishes a second viable Syncoilin knockout model and highlights the importance of further investigations to determine the role of Syncoilin in skeletal muscle.
Eva Farrero - One of the best experts on this subject based on the ideXlab platform.
-
desmin related myopathy clinical electrophysiological radiological neuropathological and genetic studies
Journal of the Neurological Sciences, 2004Co-Authors: Montse Olive, Lev G Goldfarb, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Juan Antonio Martinezmatos, Francesca Martinez, Josefina Alio, Eva FarreroAbstract:Abstract Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, αB-crystallin and amyloid βA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or αB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
-
Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.
Journal of the neurological sciences, 2004Co-Authors: Montse Olive, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Francesca Martinez, Josefina Alio, Lev Goldfarb, Juan Antonio Martínez-matos, Eva FarreroAbstract:Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
Nyamkhishig Sambuughin - One of the best experts on this subject based on the ideXlab platform.
-
desmin related myopathy clinical electrophysiological radiological neuropathological and genetic studies
Journal of the Neurological Sciences, 2004Co-Authors: Montse Olive, Lev G Goldfarb, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Juan Antonio Martinezmatos, Francesca Martinez, Josefina Alio, Eva FarreroAbstract:Abstract Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, αB-crystallin and amyloid βA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or αB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
-
Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.
Journal of the neurological sciences, 2004Co-Authors: Montse Olive, Dolores Moreno, Encarna Laforet, Ayush Dagvadorj, Nyamkhishig Sambuughin, Francesca Martinez, Josefina Alio, Lev Goldfarb, Juan Antonio Martínez-matos, Eva FarreroAbstract:Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, Syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
-
Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases
Acta Neuropathologica, 2003Co-Authors: Montse Olive, Denise Paulin, Ayush Dagvadorj, Nyamkhishig Sambuughin, Lev Goldfarb, Bertrand Goudeau, Patrick Vicart, Isidro FerrerAbstract:Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and α-actinin. In the present study, the distribution of synemin was examined using immunohistochemistry in muscle biopsy specimens from patients suffering from myofibrillar myopathy (MM, n =6), dermatomyositis (DM, n =3), inclusion body myositis (IBM, n =5), oculopharyngeal muscular dystrophy (OPD, n =3) and denervation atrophy (DA, n =3), to investigate the possible participation of this protein in the pathogenesis of various muscular diseases. Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the αB-crystallin gene; and no mutations were identified in synemin or Syncoilin genes of three patients. Synemin immunohistochemistry disclosed a faint staining corresponding to the Z-bands in the cytoplasm of control muscle fibres; in contrast, focal aggregates of synemin were seen in patients with MM. Increased synemin immunoreactivity was identified diffusely or in the subsarcolemmal space of scattered fibres in patients with DM, and in vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity was observed in target formations and atrophic fibres of patients with denervating disorders, as well as in atrophic fibres, regardless of their origin, in all patients studied. Synemin co-localised with desmin, as seen on consecutive serial sections immunostained with anti-synemin or anti-desmin antibodies. These observations demonstrate abnormal accumulations containing both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and DA. Considering the important role of synemin as one of intermediate filaments of skeletal and cardiac muscle, its destruction and accumulation in the intracellular debris suggest that synemin may participate in the pathogenesis of these disorders.
