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Mathias Gautel - One of the best experts on this subject based on the ideXlab platform.
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Phosphoregulation of the titin-cap protein Telethonin in cardiac myocytes
The Journal of biological chemistry, 2013Co-Authors: Alexandra J. Candasamy, Robert S. Haworth, Friederike Cuello, Michael Ibrahim, Sriram Aravamudhan, Marcus Krüger, Mark R. Holt, Cesare M. Terracciano, Manuel Mayr, Mathias GautelAbstract:Abstract Telethonin (also known as titin-cap or t-cap) is a muscle-specific protein whose mutation is associated with cardiac and skeletal myopathies through unknown mechanisms. Our previous work identified cardiac Telethonin as an interaction partner for the protein kinase D catalytic domain. In this study, kinase assays used in conjunction with MS and site-directed mutagenesis confirmed Telethonin as a substrate for protein kinase D and Ca2+/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites. Phosphate affinity electrophoresis and MS revealed endogenous Telethonin to exist in a constitutively bis-phosphorylated form in isolated adult rat ventricular myocytes and in mouse and rat ventricular myocardium. Following heterologous expression in myocytes by adenoviral gene transfer, wild-type Telethonin became bis-phosphorylated, whereas S157A/S161A Telethonin remained non-phosphorylated. Nevertheless, both proteins localized predominantly to the sarcomeric Z-disc, where they partially replaced endogenous Telethonin. Such partial replacement with S157A/S161A Telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca2+ transient and increased its variance. These data reveal, for the first time, that cardiac Telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal Telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca2+ transients.
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SignalingP84Phosphoregulation of the titin-cap protein Telethonin in cardiac myocytes
Cardiovascular Research, 2012Co-Authors: Alexandra J. Candasamy, Robert S. Haworth, Friederike Cuello, Manuel Mayr, Mathias Gautel, A. Boguslavsky, Michael J. Shattock, Metin AvkiranAbstract:The titin-cap protein Telethonin was previously identified by our group as an interaction partner for the protein kinase D (PKD) catalytic domain, through a yeast two-hybrid screen of a human cardiac cDNA library. In the present work, kinase assays confirmed that recombinant full-length Telethonin i
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evidence for a dimeric assembly of two titin Telethonin complexes induced by the Telethonin c terminus
Journal of Structural Biology, 2006Co-Authors: Nikos Pinotsis, Peijian Zou, Mathias Gautel, Dmitri I. Svergun, Maxim V. Petoukhov, Stephan Lange, Matthias WilmannsAbstract:Abstract The Z-disk region defines the lateral boundary of the sarcomere and requires a high level of mechanical strength to provide a stable framework for large filamentous muscle proteins. The level of complexity at this area is reflected by a large number of protein–protein interactions. Recently, we unraveled how the N-terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the N-terminal titin-binding segment of the Z-disk ligand Telethonin/T-cap [Zou, P., Pinotsis, N., Lange, S., Song, Y.H., Popov, A., Mavridis, I., Mayans, O.M., Gautel, M., Wilmanns, M., 2006. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439, 229–233]. In this contribution, we present structural data of a related complex of the titin N-terminus with full-length Telethonin. The C-terminus of Telethonin remains invisible, suggesting that it does not fold into a defined structure even in the presence of titin. In contrast to the structure with truncated Telethonin, a dimer of two titin/Telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. We further investigated the structure and dynamics of this assembly by small-angle X-ray scattering, circular dichroism, and in vivo complementation data. The data consistently indicate the involvement of the C-terminal part of Telethonin into the assembly of two titin/Telethonin complexes.
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Evidence for a dimeric assembly of two titin/Telethonin complexes induced by the Telethonin C-terminus
Journal of structural biology, 2006Co-Authors: Nikos Pinotsis, Peijian Zou, Mathias Gautel, Dmitri I. Svergun, Maxim V. Petoukhov, Stephan Lange, Matthias WilmannsAbstract:Abstract The Z-disk region defines the lateral boundary of the sarcomere and requires a high level of mechanical strength to provide a stable framework for large filamentous muscle proteins. The level of complexity at this area is reflected by a large number of protein–protein interactions. Recently, we unraveled how the N-terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the N-terminal titin-binding segment of the Z-disk ligand Telethonin/T-cap [Zou, P., Pinotsis, N., Lange, S., Song, Y.H., Popov, A., Mavridis, I., Mayans, O.M., Gautel, M., Wilmanns, M., 2006. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439, 229–233]. In this contribution, we present structural data of a related complex of the titin N-terminus with full-length Telethonin. The C-terminus of Telethonin remains invisible, suggesting that it does not fold into a defined structure even in the presence of titin. In contrast to the structure with truncated Telethonin, a dimer of two titin/Telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. We further investigated the structure and dynamics of this assembly by small-angle X-ray scattering, circular dichroism, and in vivo complementation data. The data consistently indicate the involvement of the C-terminal part of Telethonin into the assembly of two titin/Telethonin complexes.
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palindromic assembly of the giant muscle protein titin in the sarcomeric z disk
Nature, 2006Co-Authors: Nikos Pinotsis, Mathias Gautel, Stephan Lange, Y H Song, A Popov, Irene M Mavridis, Olga Mayans, M WilmannsAbstract:The Z-disk of striated and cardiac muscle sarcomeres is one of the most densely packed cellular structures in eukaryotic cells1. It provides the architectural framework for assembling and anchoring the largest known muscle filament systems by an extensive network of protein–protein interactions, requiring an extraordinary level of mechanical stability. Here we show, using X-ray crystallography, how the amino terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z-disk ligand Telethonin. The pseudosymmetric structure of Telethonin mediates a unique palindromic arrangement of two titin filaments, a type of molecular assembly previously found only in protein–DNA complexes. We have confirmed its unique architecture in vivo by protein complementation assays, and in vitro by experiments using fluorescence resonance energy transfer. The model proposed may provide a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored and aligned within complex cytoskeletal networks.
Matthias Wilmanns - One of the best experts on this subject based on the ideXlab platform.
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The titin-Telethonin complex is a directed, superstable molecular bond in the muscle Z-disk.
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Morten Bertz, Matthias Wilmanns, Matthias RiefAbstract:Mechanical stability of bonds and protein interactions has recently become accessible through single molecule mechanical experiments. So far, mechanical information about molecular bond mechanics has been largely limited to a single direction of force application. However, mechanical force acts as a vector in space and hence mechanical stability should depend on the direction of force application. In skeletal muscle, the giant protein titin is anchored in the Z-disk by Telethonin. Much of the structural integrity of the Z-disk hinges upon the titin-Telethonin bond. In this paper we show that the complex between the muscle proteins titin and Telethonin forms a highly directed molecular bond. It is designed to resist ultra-high forces if they are applied in the direction along which it is loaded under physiological conditions, while it breaks easily along other directions. Highly directed molecular bonds match in an ideal way the requirements of tissues subject to mechanical stress.
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evidence for a dimeric assembly of two titin Telethonin complexes induced by the Telethonin c terminus
Journal of Structural Biology, 2006Co-Authors: Nikos Pinotsis, Peijian Zou, Mathias Gautel, Dmitri I. Svergun, Maxim V. Petoukhov, Stephan Lange, Matthias WilmannsAbstract:Abstract The Z-disk region defines the lateral boundary of the sarcomere and requires a high level of mechanical strength to provide a stable framework for large filamentous muscle proteins. The level of complexity at this area is reflected by a large number of protein–protein interactions. Recently, we unraveled how the N-terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the N-terminal titin-binding segment of the Z-disk ligand Telethonin/T-cap [Zou, P., Pinotsis, N., Lange, S., Song, Y.H., Popov, A., Mavridis, I., Mayans, O.M., Gautel, M., Wilmanns, M., 2006. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439, 229–233]. In this contribution, we present structural data of a related complex of the titin N-terminus with full-length Telethonin. The C-terminus of Telethonin remains invisible, suggesting that it does not fold into a defined structure even in the presence of titin. In contrast to the structure with truncated Telethonin, a dimer of two titin/Telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. We further investigated the structure and dynamics of this assembly by small-angle X-ray scattering, circular dichroism, and in vivo complementation data. The data consistently indicate the involvement of the C-terminal part of Telethonin into the assembly of two titin/Telethonin complexes.
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Evidence for a dimeric assembly of two titin/Telethonin complexes induced by the Telethonin C-terminus
Journal of structural biology, 2006Co-Authors: Nikos Pinotsis, Peijian Zou, Mathias Gautel, Dmitri I. Svergun, Maxim V. Petoukhov, Stephan Lange, Matthias WilmannsAbstract:Abstract The Z-disk region defines the lateral boundary of the sarcomere and requires a high level of mechanical strength to provide a stable framework for large filamentous muscle proteins. The level of complexity at this area is reflected by a large number of protein–protein interactions. Recently, we unraveled how the N-terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the N-terminal titin-binding segment of the Z-disk ligand Telethonin/T-cap [Zou, P., Pinotsis, N., Lange, S., Song, Y.H., Popov, A., Mavridis, I., Mayans, O.M., Gautel, M., Wilmanns, M., 2006. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature 439, 229–233]. In this contribution, we present structural data of a related complex of the titin N-terminus with full-length Telethonin. The C-terminus of Telethonin remains invisible, suggesting that it does not fold into a defined structure even in the presence of titin. In contrast to the structure with truncated Telethonin, a dimer of two titin/Telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. We further investigated the structure and dynamics of this assembly by small-angle X-ray scattering, circular dichroism, and in vivo complementation data. The data consistently indicate the involvement of the C-terminal part of Telethonin into the assembly of two titin/Telethonin complexes.
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Mechanical Strength of the Titin Z1Z2-Telethonin Complex
Structure (London England : 1993), 2006Co-Authors: Eric H. Lee, Matthias Wilmanns, Nikos Pinotsis, Mu Gao, Klaus SchultenAbstract:Summary Using molecular dynamics simulations, we have explored the mechanical strength of the titin Z1Z2-Telethonin complex, namely, its ability to bear strong forces such as those encountered during passive muscle stretch. Our results show that not only does this complex resist considerable mechanical force through β strand crosslinking, suggesting that Telethonin is an important component of the N-terminal titin anchor, but also that Telethonin distributes these forces between its two joined titin Z2 domains to protect the proximal Z1 domains from bearing too much stress. Our simulations also reveal that without Telethonin, apo-titin Z1Z2 exhibits significantly decreased resistance to mechanical stress, and that the N-terminal segment of Telethonin (residues 1–89) does not exhibit a stable fold conformation when it is unbound from titin Z1Z2. Consequently, our study sheds light on a key but little studied architectural feature of biological cells—the existence of strong mechanical links that glue separate proteins together.
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The Ig Doublet Z1Z2: A Model System for the Hybrid Analysis of Conformational Dynamics in Ig Tandems from Titin
Structure (London England : 1993), 2006Co-Authors: Marco Marino, Peijian Zou, Matthias Wilmanns, Dmitri I. Svergun, Claudia Muhle-goll, Pilar Garcia, Christian Edlich, Bernd Simon, Olga MayansAbstract:Titin is a gigantic elastic filament that determines sarcomere ultrastructure and stretch response in vertebrate muscle. It folds into numerous Ig and FnIII domains connected in tandem. Data on interdomain arrangements and dynamics are essential for understanding the function of this filament. Here, we report a mechanistic analysis of the conformational dynamics of two Ig domains from the N terminus of titin, Z1Z2, by using X-ray crystallography, SAXS, NMR relaxation data, and residual dipolar couplings in combination. Z1Z2 preferentially adopts semiextended conformations in solution, with close-hinge arrangements representing low-probability states. Although interdomain contacts are not observed, the linker appears to acquire moderate rigidity via small, local hydrophobic interactions. Thus, Z1Z2 constitutes an adaptable modular system with restricted dynamics. We speculate that its preexistent conformation contributes to the selective recruitment of the binding partner Telethonin onto the repetitive surface of the filament. The structural interconversion of four Z1Z2 conformers is analyzed.
Georgine Faulkner - One of the best experts on this subject based on the ideXlab platform.
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A Mutation in Telethonin Alters Nav1.5 Function
The Journal of biological chemistry, 2008Co-Authors: Amelia Mazzone, Georgine Faulkner, Peter R. Strege, David J. Tester, Cheryl E. Bernard, Roberto De Giorgio, Jonathan C. Makielski, Vincenzo Stanghellini, Simon J. Gibbons, Michael J. AckermanAbstract:Abstract Excitable cells express a variety of ion channels that allow rapid exchange of ions with the extracellular space. Opening of Na+ channels in excitable cells results in influx of Na+ and cellular depolarization. The function of Nav1.5, an Na+ channel expressed in the heart, brain, and gastrointestinal tract, is altered by interacting proteins. The pore-forming α-subunit of this channel is encoded by SCN5A. Genetic perturbations in SCN5A cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes. Mutations in SCN5A are also associated with increased prevalence of gastrointestinal symptoms, suggesting that the Na+ channel plays a role in normal gastrointestinal physiology and that alterations in its function may cause disease. We collected blood from patients with intestinal pseudo-obstruction (a disease associated with abnormal motility in the gut) and screened for mutations in SCN5A and ion channel-interacting proteins. A 42-year-old male patient was found to have a mutation in the gene TCAP, encoding for the small protein Telethonin. Telethonin was found to be expressed in the human gastrointestinal smooth muscle, co-localized with Nav1.5, and co-immunoprecipitated with sodium channels. Expression of mutated Telethonin, when co-expressed with SCN5A in HEK 293 cells, altered steady state activation kinetics of SCN5A, resulting in a doubling of the window current. These results suggest a new role for Telethonin, namely that Telethonin is a sodium channel-interacting protein. Also, mutations in Telethonin can alter Nav1.5 kinetics and may play a role in intestinal pseudo-obstruction.
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Telethonin protein expression in neuromuscular disorders.
Biochimica et biophysica acta, 2002Co-Authors: Mariz Vainzof, Olli Carpén, E. S. Moreira, Oscar T. Suzuki, Georgine Faulkner, Georgio Valle, Alan H. Beggs, Alberto F. Ribeiro, Edmar Zanoteli, Juliana Gurgel-giannetiAbstract:Telethonin is a 19-kDa sarcomeric protein, localized to the Z-disc of skeletal and cardiac muscles. Mutations in the Telethonin gene cause limb–girdle muscular dystrophy type 2G (LGMD2G). We investigated the sarcomeric integrity of muscle fibers in LGMD2G patients, through double immunofluorescence analysis for Telethonin with three sarcomeric proteins: titin, a-actinin-2, and myotilin and observed the typical cross striation pattern, suggesting that the Z-line of the sarcomere is apparently preserved, despite the absence of Telethonin. Ultrastructural analysis confirmed the integrity of the sarcomeric architecture. The possible interaction of Telethonin with other proteins responsible for several forms of neuromuscular disorders was also analyzed. Telethonin was clearly present in the rods in nemaline myopathy (NM) muscle fibers, confirming its localization to the Z-line of the sarcomere. Muscle from patients with absent Telethonin showed normal expression for the proteins dystrophin, sarcoglycans, dysferlin, and calpain-3. Additionally, Telethonin showed normal localization in muscle biopsies from patients with LGMD2A, LGMD2B, sarcoglycanopathies, and Duchenne muscular dystrophy (DMD). Therefore, the primary deficiency of calpain-3, dysferlin, sarcoglycans, and dystrophin do not seem to alter Telethonin expression. D 2002 Elsevier Science B.V. All rights reserved.
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Dysferlin protein analysis in limb-girdle muscular dystrophies
Journal of Molecular Neuroscience, 2001Co-Authors: Mariz Vainzof, Georgine Faulkner, Giorgio Valle, Maria Rita Passos-bueno, Louise V. B. Anderson, Elizabeth M. Mcnally, Dawn B. Davis, Eloisa S. Moreira, Rita C. M. Pavanello, Mayana ZatzAbstract:Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D, 2E and 2F). The other five forms, usually causing a milder phenotype are LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2G (Telethonin), LGMD2H (9q31-11), and LGMD2I (19q13.3). We studied dysferlin expression in a total of 176 patients, from 166 LGMD families: 12 LGMD2B patients, 70 with other known forms of muscular dystrophies (LGMD2A, sarcoglycanopathies, LGMD2G), in an attempt to assess the effect of the primary gene-product deficiency on dysferlin. In addition, 94 still unclassified LGMD families were screened for dysferlin deficiency. In eight LGMD2B patients from five families, no dysferlin was observed in muscle biopsies, both through immunofluorescence (IF) and Western blot methodologies, while in two families, a very faint band was detected. Both patterns, negative or very faint bands, were concordant in patients belonging to the same families, suggesting that dysferlin deficiency is specific to LGMD2B. Myoferlin, the newly identified homologue of dysferlin was studied for the first time in LGMD2B patients. Since no difference was observed between patients mildly and severely affected, this protein do not seem to modify the phenotype in the present dysferlin-deficient patients. Dystrophin, sarcoglycans, and Telethonin were normal in all LGMD2B patients, while patients with sarcoglycanopathies (2C, 2D, and 2E), LGMD2A, LGMD2G, and DMD showed the presence of a normal dysferlin band by Western blot and a positive pattern on IF. These data suggest that there is no interaction between dysferlin and these proteins. However, calpain analysis showed a weaker band in four patients from two families with intra-familial concordance. Therefore, this secondary deficiency of calpain in LGMD2B families, may indicate an interaction between dysferlin and calpain in muscle. Dysferlin was also present in cultured myotubes, in chorionic villus, and in the skin. Dysferlin deficiency was found in 24 out of a total of 166 Brazilian AR-LGMD families screened for muscle proteins (∼14%), thus representing the second most frequent known LGMD form, after calpainopathy, in our population.
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Telethonin and other new proteins of the Z-disc of skeletal muscle.
IUBMB life, 2001Co-Authors: Georgine Faulkner, Gerolamo Lanfranchi, Giorgio ValleAbstract:This brief review outlines some of the most relevant proteins of the Z-disc and the complex network of interactions that link them together in a stable structure. Apart from the well-known Z-disc proteins such as actin, cap-Z, titin, nebulin, and alpha-actinin 2, several other Z-disc proteins have been recently discovered, including Telethonin and myotilin that have been linked to limb girdle muscular dystrophies. Some proteins including ALP and ZASP have known interaction domains (PDZ and LIM motifs), whereas others like FATZ have no canonical interaction domains, although they are known to bind several proteins. Another new Z-disc protein is gamma-filamin that could provide a link between the plasma membrane and myofibrils because it binds directly to gamma- and delta-sarcoglycans and indirectly to alpha-actinin 2 via FATZ and myotilin. A greater knowledge of Z-disc proteins and their interactions is essential for understanding their role in the structure and function of muscle.
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Dysferlin protein analysis in limb-girdle muscular dystrophies.
Journal of molecular neuroscience : MN, 2001Co-Authors: Mariz Vainzof, E. S. Moreira, Georgine Faulkner, Giorgio Valle, Rita De Cássia M. Pavanello, Maria Rita Passos-bueno, Louise V. B. Anderson, Elizabeth M. Mcnally, Dawn B. Davis, Mayana ZatzAbstract:Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D, 2E and 2F). The other five forms, usually causing a milder phenotype are LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2G (Telethonin), LGMD2H (9q31-11), and LGMD21 (19q13.3). We studied dysferlin expression in a total of 176 patients, from 166 LGMD families: 12 LGMD2B patients, 70 with other known forms of muscular dystrophies (LGMD2A, sarcoglycanopathies, LGMD2G), in an attempt to assess the effect of the primary gene-product deficiency on dysferlin. In addition, 94 still unclassified LGMD families were screened for dysferlin deficiency. In eight LGMD2B patients from five families, no dysferlin was observed in muscle biopsies, both through immunofluorescence (IF) and Western blot methodologies, while in two families, a very faint band was detected. Both patterns, negative or very faint bands, were concordant in patients belonging to the same families, suggesting that dysferlin deficiency is specific to LGMD2B. Myoferlin, the newly identified homologue of dysferlin was studied for the first time in LGMD2B patients. Since no difference was observed between patients mildly and severely affected, this protein do not seem to modify the phenotype in the present dysferlin-deficient patients. Dystrophin, sarcoglycans, and Telethonin were normal in all LGMD2B patients, while patients with sarcoglycanopathies (2C, 2D, and 2E), LGMD2A, LGMD2G, and DMD showed the presence of a normal dysferlin band by Western blot and a positive pattern on IF. These data suggest that there is no interaction between dysferlin and these proteins. However, calpain analysis showed a weaker band in four patients from two families with intra-familial concordance. Therefore, this secondary deficiency of calpain in LGMD2B families, may indicate an interaction between dysferlin and calpain in muscle. Dysferlin was also present in cultured myotubes, in chorionic villus, and in the skin. Dysferlin deficiency was found in 24 out of a total of 166 Brazilian AR-LGMD families screened for muscle proteins (approximately 14%), thus representing the second most frequent known LGMD form, after calpainopathy, in our population.
Gerolamo Lanfranchi - One of the best experts on this subject based on the ideXlab platform.
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Expression profiling characterization of laminin α-2 positive MDC
Biochemical and Biophysical Research Communications, 2006Co-Authors: Caterina Millino, Milena Bellin, Marina Fanin, Chiara Romualdi, Elena Pegoraro, Corrado Angelini, Gerolamo LanfranchiAbstract:Abstract In the Caucasian population, patients affected by the most frequent forms of congenital muscular dystrophies (MDC) are commonly divided into two groups. The first is characterized by mutations of the gene for the laminin α-2 (LAMA2). The second is positive for this protein, highly heterogeneous, and has no specific genetic defect associated yet. We studied the skeletal muscle transcriptome of four LAMA2 deficient and six LAMA2 positive MDC patients by cDNA microarrays. The expression profiling defined two patients groups: one mild and one severe phenotype. This result was in agreement with histopathological features but only partially with the clinical classification. The mild phenotype is characterized by a delayed maturation from slow to fast muscle fibers. Other muscle transcripts, such as Telethonin, myosin light-chains 3 and 1 V, are underexpressed in this group. We suggest that expression profiling will provide important information to improve our understanding of the molecular basis of laminin α-2 positive MDC.
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Telethonin and other new proteins of the Z-disc of skeletal muscle.
IUBMB life, 2001Co-Authors: Georgine Faulkner, Gerolamo Lanfranchi, Giorgio ValleAbstract:This brief review outlines some of the most relevant proteins of the Z-disc and the complex network of interactions that link them together in a stable structure. Apart from the well-known Z-disc proteins such as actin, cap-Z, titin, nebulin, and alpha-actinin 2, several other Z-disc proteins have been recently discovered, including Telethonin and myotilin that have been linked to limb girdle muscular dystrophies. Some proteins including ALP and ZASP have known interaction domains (PDZ and LIM motifs), whereas others like FATZ have no canonical interaction domains, although they are known to bind several proteins. Another new Z-disc protein is gamma-filamin that could provide a link between the plasma membrane and myofibrils because it binds directly to gamma- and delta-sarcoglycans and indirectly to alpha-actinin 2 via FATZ and myotilin. A greater knowledge of Z-disc proteins and their interactions is essential for understanding their role in the structure and function of muscle.
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Telethonin, a novel sarcomeric protein of heart and skeletal muscle
FEBS letters, 1997Co-Authors: Giorgio Valle, Georgine Faulkner, A. De Antoni, Beniamina Pacchioni, Alberto Pallavicini, D. Pandolfo, Natascia Tiso, Stefano Toppo, S. Trevisan, Gerolamo LanfranchiAbstract:In this paper we describe a novel 19 kDa sarcomeric protein named Telethonin. The cDNA sequence discloses an open reading frame of 167 amino acids that does not resemble any known protein. Antibodies against a recombinant Telethonin fragment were used for Western blot analysis, confirming the presence of this 19 kDa protein in heart and skeletal muscle and revealing an immunofluorescence pattern typical of sarcomeric proteins, overlapping myosin. The frequency of specific cDNA clones in different libraries indicates that the Telethonin transcript is amongst the most abundant in skeletal muscle. In human, Telethonin maps at 17q12, adjacent to the phenylethanolamine N-methyltransferase gene.
Michael J. Ackerman - One of the best experts on this subject based on the ideXlab platform.
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A Mutation in Telethonin Alters Nav1.5 Function
The Journal of biological chemistry, 2008Co-Authors: Amelia Mazzone, Georgine Faulkner, Peter R. Strege, David J. Tester, Cheryl E. Bernard, Roberto De Giorgio, Jonathan C. Makielski, Vincenzo Stanghellini, Simon J. Gibbons, Michael J. AckermanAbstract:Abstract Excitable cells express a variety of ion channels that allow rapid exchange of ions with the extracellular space. Opening of Na+ channels in excitable cells results in influx of Na+ and cellular depolarization. The function of Nav1.5, an Na+ channel expressed in the heart, brain, and gastrointestinal tract, is altered by interacting proteins. The pore-forming α-subunit of this channel is encoded by SCN5A. Genetic perturbations in SCN5A cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes. Mutations in SCN5A are also associated with increased prevalence of gastrointestinal symptoms, suggesting that the Na+ channel plays a role in normal gastrointestinal physiology and that alterations in its function may cause disease. We collected blood from patients with intestinal pseudo-obstruction (a disease associated with abnormal motility in the gut) and screened for mutations in SCN5A and ion channel-interacting proteins. A 42-year-old male patient was found to have a mutation in the gene TCAP, encoding for the small protein Telethonin. Telethonin was found to be expressed in the human gastrointestinal smooth muscle, co-localized with Nav1.5, and co-immunoprecipitated with sodium channels. Expression of mutated Telethonin, when co-expressed with SCN5A in HEK 293 cells, altered steady state activation kinetics of SCN5A, resulting in a doubling of the window current. These results suggest a new role for Telethonin, namely that Telethonin is a sodium channel-interacting protein. Also, mutations in Telethonin can alter Nav1.5 kinetics and may play a role in intestinal pseudo-obstruction.
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genotype phenotype relationships involving hypertrophic cardiomyopathy associated mutations in titin muscle lim protein and Telethonin
Molecular Genetics and Metabolism, 2006Co-Authors: Martijn J Bos, David J. Tester, Rainer N. Poley, Matteo Vatta, Jeffrey A. Towbin, Bernard J. Gersh, Steve R. Ommen, Michael J. AckermanAbstract:Background TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded Telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte’s stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.
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Genotype—phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and Telethonin
Molecular genetics and metabolism, 2005Co-Authors: J. Martijn Bos, David J. Tester, Rainer N. Poley, Matteo Vatta, Jeffrey A. Towbin, Bernard J. Gersh, Steve R. Ommen, Michael J. AckermanAbstract:Background TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded Telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte’s stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center.
