FranceBresilV1, Main, Exploration, bibRecord, 000461

K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

Identifieur interne : 000461 ( Main/Exploration ); précédent : 000460; suivant : 000462

K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

Auteurs : RBID : Pascal:13-0124491

Descripteurs français

Pascal (Inist)
- Myopathie némaline, Pathologie du système nerveux, Mutation, Calcium, Sensibilité, Congénital, Contraction musculaire, Articulation, Contracture.
Wicri :
- topic : Calcium.

English descriptors

KwdEn :
- Calcium, Congenital, Contracture, Joint, Muscle contraction, Mutation, Nemaline myopathy, Nervous system diseases, Sensitivity.

Abstract

Mutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved lysine residue near the N-terminus of β-tropomyosin, which is predicted to disrupt head-to-tail polymerization of tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the troponin/tropomyosin-dependent calcium switch of muscle. Joint contractures may stem from chronic muscle hypercontraction due to increased myofibrillar calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from therapies that reduce skeletal muscle calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity.

Links toward previous steps (curation, corpus...)

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Le document en format XML

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<author><name>NAN YANG</name>
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<affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Département de Neurologie, Hôpitaux Universitaires de Strasbourg</s1>
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<author><name sortKey="Ravenscroft, Gianina" uniqKey="Ravenscroft G">Gianina Ravenscroft</name>
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<author><name sortKey="Mcnamara, Elyshia" uniqKey="Mcnamara E">Elyshia Mcnamara</name>
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<author><name sortKey="Nowak, Kristen J" uniqKey="Nowak K">Kristen J. Nowak</name>
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<author><name sortKey="Laing, Nigel G" uniqKey="Laing N">Nigel G. Laing</name>
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<author><name sortKey="Wallgren Pettersson, Carina" uniqKey="Wallgren Pettersson C">Carina Wallgren-Pettersson</name>
<affiliation wicri:level="1"><inist:fA14 i1="06"><s1>The Folkhälsan Institute of Genetics and the Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki</s1>
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<author><name sortKey="Trewhella, Jill" uniqKey="Trewhella J">Jill Trewhella</name>
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<author><name sortKey="Marston, Steve" uniqKey="Marston S">Steve Marston</name>
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<author><name sortKey="Ottenheijm, Coen" uniqKey="Ottenheijm C">Coen Ottenheijm</name>
<affiliation wicri:level="1"><inist:fA14 i1="15"><s1>Department of Physiology, VU University Medical Centre</s1>
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<author><name sortKey="North, Kathryn N" uniqKey="North K">Kathryn N. North</name>
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<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Discipline of Paediatrics and Child Health, University of Sydney</s1>
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<author><name sortKey="Clarke, Nigel F" uniqKey="Clarke N">Nigel F. Clarke</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead</s1>
<s2>Sydney, NSW 2145</s2>
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<country>Australie</country>
<wicri:noRegion>Sydney, NSW 2145</wicri:noRegion>
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<affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Discipline of Paediatrics and Child Health, University of Sydney</s1>
<s2>Sydney, NSW 2006</s2>
<s3>AUS</s3>
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<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>25 aut.</sZ>
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<country>Australie</country>
<wicri:noRegion>Sydney, NSW 2006</wicri:noRegion>
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</titleStmt>
<publicationStmt><idno type="inist">13-0124491</idno>
<date when="2013">2013</date>
<idno type="stanalyst">PASCAL 13-0124491 INIST</idno>
<idno type="RBID">Pascal:13-0124491</idno>
<idno type="wicri:Area/Main/Corpus">000639</idno>
<idno type="wicri:Area/Main/Curation">002217</idno>
<idno type="wicri:Area/Main/Exploration">000461</idno>
</publicationStmt>
<seriesStmt><idno type="ISSN">0006-8950</idno>
<title level="j" type="abbreviated">Brain</title>
<title level="j" type="main">Brain</title>
</seriesStmt>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Calcium</term>
<term>Congenital</term>
<term>Contracture</term>
<term>Joint</term>
<term>Muscle contraction</term>
<term>Mutation</term>
<term>Nemaline myopathy</term>
<term>Nervous system diseases</term>
<term>Sensitivity</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Myopathie némaline</term>
<term>Pathologie du   système nerveux</term>
<term>Mutation</term>
<term>Calcium</term>
<term>Sensibilité</term>
<term>Congénital</term>
<term>Contraction musculaire</term>
<term>Articulation</term>
<term>Contracture</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Calcium</term>
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<front><div type="abstract" xml:lang="en">Mutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved lysine residue near the N-terminus of β-tropomyosin, which is predicted to disrupt head-to-tail polymerization of tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the troponin/tropomyosin-dependent calcium switch of muscle. Joint contractures may stem from chronic muscle hypercontraction due to increased myofibrillar calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from therapies that reduce skeletal muscle calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity.</div>
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K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

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