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Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I

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BOGOMOLOVAS, Julius, Jennifer FLEMING, Brian ANDERSON, Rhys WILLIAMS, Stephan LANGE, Bernd SIMON, Muzamil KHAN, Rüdiger RUDOLF, Barbara FRANKE, Belinda BULLARD, Daniel RIGDEN, Henk GRANZIER, Siegfried LABEIT, Olga Maria MAYANS CARRILLO, 2016. Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I. In: Open biology. 6(9), 160114. eISSN 2046-2441. Available under: doi: 10.1098/rsob.160114

@article{Bogomolovas2016Explo-36563, title={Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I}, year={2016}, doi={10.1098/rsob.160114}, number={9}, volume={6}, journal={Open biology}, author={Bogomolovas, Julius and Fleming, Jennifer and Anderson, Brian and Williams, Rhys and Lange, Stephan and Simon, Bernd and Khan, Muzamil and Rudolf, Rüdiger and Franke, Barbara and Bullard, Belinda and Rigden, Daniel and Granzier, Henk and Labeit, Siegfried and Mayans Carrillo, Olga Maria}, note={Article Number: 160114} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/36563"> <dc:creator>Williams, Rhys</dc:creator> <dc:creator>Khan, Muzamil</dc:creator> <dc:contributor>Anderson, Brian</dc:contributor> <dc:contributor>Bullard, Belinda</dc:contributor> <dc:language>eng</dc:language> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:creator>Anderson, Brian</dc:creator> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/36563/1/Bogomolovas_0-383132.pdf"/> <dc:contributor>Franke, Barbara</dc:contributor> <dc:creator>Mayans Carrillo, Olga Maria</dc:creator> <dcterms:title>Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I</dcterms:title> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dcterms:issued>2016</dcterms:issued> <dcterms:rights rdf:resource="http://nbn-resolving.de/urn:nbn:de:bsz:352-20150914100631302-4485392-8"/> <dc:contributor>Mayans Carrillo, Olga Maria</dc:contributor> <dc:creator>Bogomolovas, Julius</dc:creator> <dc:creator>Labeit, Siegfried</dc:creator> <dc:creator>Simon, Bernd</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2017-01-11T09:54:39Z</dcterms:available> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2017-01-11T09:54:39Z</dc:date> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:contributor>Labeit, Siegfried</dc:contributor> <dc:creator>Rudolf, Rüdiger</dc:creator> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Franke, Barbara</dc:creator> <dc:contributor>Fleming, Jennifer</dc:contributor> <dc:contributor>Williams, Rhys</dc:contributor> <dc:creator>Granzier, Henk</dc:creator> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/36563"/> <dcterms:abstract xml:lang="eng">Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin's I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected.</dcterms:abstract> <dc:creator>Rigden, Daniel</dc:creator> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/36563/1/Bogomolovas_0-383132.pdf"/> <dc:contributor>Khan, Muzamil</dc:contributor> <dc:contributor>Lange, Stephan</dc:contributor> <dc:creator>Fleming, Jennifer</dc:creator> <dc:creator>Lange, Stephan</dc:creator> <dc:contributor>Granzier, Henk</dc:contributor> <dc:contributor>Simon, Bernd</dc:contributor> <dc:contributor>Bogomolovas, Julius</dc:contributor> <dc:contributor>Rudolf, Rüdiger</dc:contributor> <dc:creator>Bullard, Belinda</dc:creator> <dc:contributor>Rigden, Daniel</dc:contributor> </rdf:Description> </rdf:RDF>

Dateiabrufe seit 11.01.2017 (Informationen über die Zugriffsstatistik)

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