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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy</title><author><name sortKey="De Winter, Josine M" sort="De Winter, Josine M" uniqKey="De Winter J" first="Josine M." last="De Winter">Josine M. De Winter</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Joureau, Barbara" sort="Joureau, Barbara" uniqKey="Joureau B" first="Barbara" last="Joureau">Barbara Joureau</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Lee, Eun Jeong" sort="Lee, Eun Jeong" uniqKey="Lee E" first="Eun-Jeong" last="Lee">Eun-Jeong Lee</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Kiss, Balazs" sort="Kiss, Balazs" uniqKey="Kiss B" first="Balázs" last="Kiss">Balázs Kiss</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Yuen, Michaela" sort="Yuen, Michaela" uniqKey="Yuen M" first="Michaela" last="Yuen">Michaela Yuen</name><affiliation><nlm:aff id="A3">Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Gupta, Vandana A" sort="Gupta, Vandana A" uniqKey="Gupta V" first="Vandana A." last="Gupta">Vandana A. Gupta</name><affiliation><nlm:aff id="A5">Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Pappas, Christopher T" sort="Pappas, Christopher T" uniqKey="Pappas C" first="Christopher T." last="Pappas">Christopher T. Pappas</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Gregorio, Carol C" sort="Gregorio, Carol C" uniqKey="Gregorio C" first="Carol C." last="Gregorio">Carol C. Gregorio</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Stienen, Ger J M" sort="Stienen, Ger J M" uniqKey="Stienen G" first="Ger J. M." last="Stienen">Ger J. M. Stienen</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Edvardson, Simon" sort="Edvardson, Simon" uniqKey="Edvardson S" first="Simon" last="Edvardson">Simon Edvardson</name><affiliation><nlm:aff id="A7">Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel</nlm:aff></affiliation></author><author><name sortKey="Wallgren Pettersson, Carina" sort="Wallgren Pettersson, Carina" uniqKey="Wallgren Pettersson C" first="Carina" last="Wallgren-Pettersson">Carina Wallgren-Pettersson</name><affiliation><nlm:aff id="A8">Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Lehtokari, Vilma Lotta" sort="Lehtokari, Vilma Lotta" uniqKey="Lehtokari V" first="Vilma-Lotta" last="Lehtokari">Vilma-Lotta Lehtokari</name><affiliation><nlm:aff id="A8">Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Pelin, Katarina" sort="Pelin, Katarina" uniqKey="Pelin K" first="Katarina" last="Pelin">Katarina Pelin</name><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Malfatti, Edoardo" sort="Malfatti, Edoardo" uniqKey="Malfatti E" first="Edoardo" last="Malfatti">Edoardo Malfatti</name><affiliation><nlm:aff id="A11">Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Romero, Norma B" sort="Romero, Norma B" uniqKey="Romero N" first="Norma B." last="Romero">Norma B. Romero</name><affiliation><nlm:aff id="A11">Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Van Engelen, Baziel G" sort="Van Engelen, Baziel G" uniqKey="Van Engelen B" first="Baziel G." last="Van Engelen">Baziel G. Van Engelen</name><affiliation><nlm:aff id="A12">Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Voermans, Nicol C" sort="Voermans, Nicol C" uniqKey="Voermans N" first="Nicol C." last="Voermans">Nicol C. Voermans</name><affiliation><nlm:aff id="A12">Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Donkervoort, Sandra" sort="Donkervoort, Sandra" uniqKey="Donkervoort S" first="Sandra" last="Donkervoort">Sandra Donkervoort</name><affiliation><nlm:aff id="A13">Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Bonnemann, C G" sort="Bonnemann, C G" uniqKey="Bonnemann C" first="C. G." last="Bönnemann">C. G. Bönnemann</name><affiliation><nlm:aff id="A13">Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Clarke, Nigel F" sort="Clarke, Nigel F" uniqKey="Clarke N" first="Nigel F." last="Clarke">Nigel F. Clarke</name><affiliation><nlm:aff id="A3">Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H." last="Beggs">Alan H. Beggs</name><affiliation><nlm:aff id="A5">Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Granzier, Henk" sort="Granzier, Henk" uniqKey="Granzier H" first="Henk" last="Granzier">Henk Granzier</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Ottenheijm, Coen A C" sort="Ottenheijm, Coen A C" uniqKey="Ottenheijm C" first="Coen A. C." last="Ottenheijm">Coen A. C. Ottenheijm</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27074222</idno><idno type="pmc">4911820</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911820</idno><idno type="RBID">PMC:4911820</idno><idno type="doi">10.1002/ana.24654</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">001F76</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001F76</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy</title><author><name sortKey="De Winter, Josine M" sort="De Winter, Josine M" uniqKey="De Winter J" first="Josine M." last="De Winter">Josine M. De Winter</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Joureau, Barbara" sort="Joureau, Barbara" uniqKey="Joureau B" first="Barbara" last="Joureau">Barbara Joureau</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Lee, Eun Jeong" sort="Lee, Eun Jeong" uniqKey="Lee E" first="Eun-Jeong" last="Lee">Eun-Jeong Lee</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Kiss, Balazs" sort="Kiss, Balazs" uniqKey="Kiss B" first="Balázs" last="Kiss">Balázs Kiss</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Yuen, Michaela" sort="Yuen, Michaela" uniqKey="Yuen M" first="Michaela" last="Yuen">Michaela Yuen</name><affiliation><nlm:aff id="A3">Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Gupta, Vandana A" sort="Gupta, Vandana A" uniqKey="Gupta V" first="Vandana A." last="Gupta">Vandana A. Gupta</name><affiliation><nlm:aff id="A5">Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Pappas, Christopher T" sort="Pappas, Christopher T" uniqKey="Pappas C" first="Christopher T." last="Pappas">Christopher T. Pappas</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Gregorio, Carol C" sort="Gregorio, Carol C" uniqKey="Gregorio C" first="Carol C." last="Gregorio">Carol C. Gregorio</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Stienen, Ger J M" sort="Stienen, Ger J M" uniqKey="Stienen G" first="Ger J. M." last="Stienen">Ger J. M. Stienen</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Edvardson, Simon" sort="Edvardson, Simon" uniqKey="Edvardson S" first="Simon" last="Edvardson">Simon Edvardson</name><affiliation><nlm:aff id="A7">Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel</nlm:aff></affiliation></author><author><name sortKey="Wallgren Pettersson, Carina" sort="Wallgren Pettersson, Carina" uniqKey="Wallgren Pettersson C" first="Carina" last="Wallgren-Pettersson">Carina Wallgren-Pettersson</name><affiliation><nlm:aff id="A8">Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Lehtokari, Vilma Lotta" sort="Lehtokari, Vilma Lotta" uniqKey="Lehtokari V" first="Vilma-Lotta" last="Lehtokari">Vilma-Lotta Lehtokari</name><affiliation><nlm:aff id="A8">Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Pelin, Katarina" sort="Pelin, Katarina" uniqKey="Pelin K" first="Katarina" last="Pelin">Katarina Pelin</name><affiliation><nlm:aff id="A9">Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Malfatti, Edoardo" sort="Malfatti, Edoardo" uniqKey="Malfatti E" first="Edoardo" last="Malfatti">Edoardo Malfatti</name><affiliation><nlm:aff id="A11">Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Romero, Norma B" sort="Romero, Norma B" uniqKey="Romero N" first="Norma B." last="Romero">Norma B. Romero</name><affiliation><nlm:aff id="A11">Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Van Engelen, Baziel G" sort="Van Engelen, Baziel G" uniqKey="Van Engelen B" first="Baziel G." last="Van Engelen">Baziel G. Van Engelen</name><affiliation><nlm:aff id="A12">Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Voermans, Nicol C" sort="Voermans, Nicol C" uniqKey="Voermans N" first="Nicol C." last="Voermans">Nicol C. Voermans</name><affiliation><nlm:aff id="A12">Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Donkervoort, Sandra" sort="Donkervoort, Sandra" uniqKey="Donkervoort S" first="Sandra" last="Donkervoort">Sandra Donkervoort</name><affiliation><nlm:aff id="A13">Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Bonnemann, C G" sort="Bonnemann, C G" uniqKey="Bonnemann C" first="C. G." last="Bönnemann">C. G. Bönnemann</name><affiliation><nlm:aff id="A13">Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD</nlm:aff></affiliation></author><author><name sortKey="Clarke, Nigel F" sort="Clarke, Nigel F" uniqKey="Clarke N" first="Nigel F." last="Clarke">Nigel F. Clarke</name><affiliation><nlm:aff id="A3">Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, New South Wales, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia</nlm:aff></affiliation></author><author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H." last="Beggs">Alan H. Beggs</name><affiliation><nlm:aff id="A5">Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA</nlm:aff></affiliation></author><author><name sortKey="Granzier, Henk" sort="Granzier, Henk" uniqKey="Granzier H" first="Henk" last="Granzier">Henk Granzier</name><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author><author><name sortKey="Ottenheijm, Coen A C" sort="Ottenheijm, Coen A C" uniqKey="Ottenheijm C" first="Coen A. C." last="Ottenheijm">Coen A. C. Ottenheijm</name><affiliation><nlm:aff id="A1">Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</nlm:aff></affiliation></author></analytic><series><title level="j">Annals of neurology</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objective</title><p id="P2">Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation.</p></sec><sec id="S2"><title>Methods</title><p id="P3">We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in <italic>NEB</italic>, <italic>ACTA1</italic>, <italic>TPM2</italic>, <italic>TPM3</italic>, <italic>TNNT1</italic>, <italic>KBTBD13</italic>, <italic>KLHL40</italic>, and <italic>KLHL41</italic>.</p></sec><sec id="S3"><title>Results</title><p id="P4">Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in <italic>NEB</italic> and <italic>ACTA1</italic>, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional <italic>Neb</italic> knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap.</p></sec><sec id="S4"><title>Interpretation</title><p id="P5">These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">7707449</journal-id><journal-id journal-id-type="pubmed-jr-id">656</journal-id><journal-id journal-id-type="nlm-ta">Ann Neurol</journal-id><journal-id journal-id-type="iso-abbrev">Ann. Neurol.</journal-id><journal-title-group><journal-title>Annals of neurology</journal-title></journal-title-group><issn pub-type="ppub">0364-5134</issn><issn pub-type="epub">1531-8249</issn></journal-meta><article-meta><article-id pub-id-type="pmid">27074222</article-id><article-id pub-id-type="pmc">4911820</article-id><article-id pub-id-type="doi">10.1002/ana.24654</article-id><article-id pub-id-type="manuscript">NIHMS793763</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mutation-Specific Effects on Thin Filament Length in Thin Filament Myopathy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>de Winter</surname><given-names>Josine M.</given-names></name><degrees>MS</degrees><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Joureau</surname><given-names>Barbara</given-names></name><degrees>MS</degrees><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Eun-Jeong</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kiss</surname><given-names>Balázs</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yuen</surname><given-names>Michaela</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gupta</surname><given-names>Vandana A.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pappas</surname><given-names>Christopher T.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gregorio</surname><given-names>Carol C.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Stienen</surname><given-names>Ger J. M.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Edvardson</surname><given-names>Simon</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Wallgren-Pettersson</surname><given-names>Carina</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Lehtokari</surname><given-names>Vilma-Lotta</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A8">8</xref><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Pelin</surname><given-names>Katarina</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A9">9</xref><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Malfatti</surname><given-names>Edoardo</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Romero</surname><given-names>Norma B.</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>van Engelen</surname><given-names>Baziel G.</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Voermans</surname><given-names>Nicol C.</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Donkervoort</surname><given-names>Sandra</given-names></name><degrees>MS, CGC</degrees><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Bönnemann</surname><given-names>C. G.</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="A13">13</xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Nigel F.</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A4">4</xref><xref ref-type="author-notes" rid="FN4">†</xref></contrib><contrib contrib-type="author"><name><surname>Beggs</surname><given-names>Alan H.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Granzier</surname><given-names>Henk</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ottenheijm</surname><given-names>Coen A. C.</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands</aff><aff id="A2"><label>2</label>Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ</aff><aff id="A3"><label>3</label>Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, New South Wales, Australia</aff><aff id="A4"><label>4</label>Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia</aff><aff id="A5"><label>5</label>Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA</aff><aff id="A6"><label>6</label>Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands</aff><aff id="A7"><label>7</label>Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel</aff><aff id="A8"><label>8</label>Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland</aff><aff id="A9"><label>9</label>Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland</aff><aff id="A10"><label>10</label>Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland</aff><aff id="A11"><label>11</label>Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France</aff><aff id="A12"><label>12</label>Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands</aff><aff id="A13"><label>13</label>Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD</aff><author-notes><corresp id="CR1">Address correspondence to Dr Ottenheijm, Department of Physiology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands. <email>c.ottenheijm@vumc.nl</email></corresp><fn fn-type="deceased" id="FN4"><label>†</label><p id="P1">Dr Nigel F. Clarke is deceased.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>11</day><month>6</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>30</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="ppub"><month>6</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>6</month><year>2016</year></pub-date><volume>79</volume><issue>6</issue><fpage>959</fpage><lpage>969</lpage><pmc-comment>elocation-id from pubmed: 10.1002/ana.24654</pmc-comment>
<abstract><sec id="S1"><title>Objective</title><p id="P2">Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation.</p></sec><sec id="S2"><title>Methods</title><p id="P3">We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in <italic>NEB</italic>, <italic>ACTA1</italic>, <italic>TPM2</italic>, <italic>TPM3</italic>, <italic>TNNT1</italic>, <italic>KBTBD13</italic>, <italic>KLHL40</italic>, and <italic>KLHL41</italic>.</p></sec><sec id="S3"><title>Results</title><p id="P4">Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in <italic>NEB</italic> and <italic>ACTA1</italic>, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional <italic>Neb</italic> knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap.</p></sec><sec id="S4"><title>Interpretation</title><p id="P5">These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths.</p></sec></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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