Alpha-cardiac actin mutations produce atrial septal defects
Identifieur interne : 001501 ( Istex/Corpus ); précédent : 001500; suivant : 001502Alpha-cardiac actin mutations produce atrial septal defects
Auteurs : Hans Matsson ; Jacqueline Eason ; Carol S. Bookwalter ; Joakim Klar ; Peter Gustavsson ; Jan Sunnegrdh ; Henrik Enell ; Anders Jonzon ; Miikka Vikkula ; Ilse Gutierrez ; Javier Granados-Riveron ; Mark Pope ; Frances Bulock ; Jane Cox ; Thelma E. Robinson ; Feifei Song ; David J. Brook ; Steven Marston ; Kathleen M. Trybus ; Niklas DahlSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2008-01-15.
Abstract
Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.
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DOI: 10.1093/hmg/ddm302
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Bookwalter</name><affiliation><mods:affiliation>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</mods:affiliation></affiliation></author><author><name sortKey="Klar, Joakim" sort="Klar, Joakim" uniqKey="Klar J" first="Joakim" last="Klar">Joakim Klar</name><affiliation><mods:affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Gustavsson, Peter" sort="Gustavsson, Peter" uniqKey="Gustavsson P" first="Peter" last="Gustavsson">Peter Gustavsson</name><affiliation><mods:affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Sunnegrdh, Jan" sort="Sunnegrdh, Jan" uniqKey="Sunnegrdh J" first="Jan" last="Sunnegrdh">Jan Sunnegrdh</name><affiliation><mods:affiliation>The Queen Silvia Childrens Hospital, S-416 85 Gteborg, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Enell, Henrik" sort="Enell, Henrik" uniqKey="Enell H" first="Henrik" last="Enell">Henrik Enell</name><affiliation><mods:affiliation>Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Jonzon, Anders" sort="Jonzon, Anders" uniqKey="Jonzon A" first="Anders" last="Jonzon">Anders Jonzon</name><affiliation><mods:affiliation>Childrens Hospital, Uppsala University, S-75185 Uppsala, Sweden</mods:affiliation></affiliation></author><author><name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name><affiliation><mods:affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Gutierrez, Ilse" sort="Gutierrez, Ilse" uniqKey="Gutierrez I" first="Ilse" last="Gutierrez">Ilse Gutierrez</name><affiliation><mods:affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Granados Riveron, Javier" sort="Granados Riveron, Javier" uniqKey="Granados Riveron J" first="Javier" last="Granados-Riveron">Javier Granados-Riveron</name><affiliation><mods:affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</mods:affiliation></affiliation></author><author><name sortKey="Pope, Mark" sort="Pope, Mark" uniqKey="Pope M" first="Mark" last="Pope">Mark Pope</name><affiliation><mods:affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</mods:affiliation></affiliation></author><author><name sortKey="Bulock, Frances" sort="Bulock, Frances" uniqKey="Bulock F" first="Frances" last="Bulock">Frances Bulock</name><affiliation><mods:affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</mods:affiliation></affiliation></author><author><name sortKey="Cox, Jane" sort="Cox, Jane" uniqKey="Cox J" first="Jane" last="Cox">Jane Cox</name><affiliation><mods:affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</mods:affiliation></affiliation></author><author><name sortKey="Robinson, Thelma E" sort="Robinson, Thelma E" uniqKey="Robinson T" first="Thelma E" last="Robinson">Thelma E. Robinson</name><affiliation><mods:affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</mods:affiliation></affiliation></author><author><name sortKey="Song, Feifei" sort="Song, Feifei" uniqKey="Song F" first="Feifei" last="Song">Feifei Song</name><affiliation><mods:affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</mods:affiliation></affiliation></author><author><name sortKey="Brook, David J" sort="Brook, David J" uniqKey="Brook D" first="David J" last="Brook">David J. Brook</name><affiliation><mods:affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</mods:affiliation></affiliation></author><author><name sortKey="Marston, Steven" sort="Marston, Steven" uniqKey="Marston S" first="Steven" last="Marston">Steven Marston</name><affiliation><mods:affiliation>National Heart and Lung Institute, Imperial College, SW3 6LY London, UK</mods:affiliation></affiliation></author><author><name sortKey="Trybus, Kathleen M" sort="Trybus, Kathleen M" uniqKey="Trybus K" first="Kathleen M." last="Trybus">Kathleen M. Trybus</name><affiliation><mods:affiliation>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</mods:affiliation></affiliation></author><author><name sortKey="Dahl, Niklas" sort="Dahl, Niklas" uniqKey="Dahl N" first="Niklas" last="Dahl">Niklas Dahl</name><affiliation><mods:affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: niklas.dahl@genpat.uu.se</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-01-15">2008-01-15</date><biblScope unit="volume">17</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="256">256</biblScope><biblScope unit="page" to="265">265</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">5E2AE62A40723AD75DBFD4902D07A47F264FC6F1</idno><idno type="DOI">10.1093/hmg/ddm302</idno><idno type="ArticleID">ddm302</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Hans Matsson</name><affiliations><json:string>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</json:string></affiliations></json:item><json:item><name>Jacqueline Eason</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>Carol S. Bookwalter</name><affiliations><json:string>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</json:string></affiliations></json:item><json:item><name>Joakim Klar</name><affiliations><json:string>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</json:string></affiliations></json:item><json:item><name>Peter Gustavsson</name><affiliations><json:string>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</json:string></affiliations></json:item><json:item><name>Jan Sunnegrdh</name><affiliations><json:string>The Queen Silvia Childrens Hospital, S-416 85 Gteborg, Sweden</json:string></affiliations></json:item><json:item><name>Henrik Enell</name><affiliations><json:string>Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad, Sweden</json:string></affiliations></json:item><json:item><name>Anders Jonzon</name><affiliations><json:string>Childrens Hospital, Uppsala University, S-75185 Uppsala, Sweden</json:string></affiliations></json:item><json:item><name>Miikka Vikkula</name><affiliations><json:string>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</json:string></affiliations></json:item><json:item><name>Ilse Gutierrez</name><affiliations><json:string>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</json:string></affiliations></json:item><json:item><name>Javier Granados-Riveron</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>Mark Pope</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>Frances BuLock</name><affiliations><json:string>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</json:string></affiliations></json:item><json:item><name>Jane Cox</name><affiliations><json:string>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</json:string></affiliations></json:item><json:item><name>Thelma E Robinson</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>Feifei Song</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>David J Brook</name><affiliations><json:string>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</json:string></affiliations></json:item><json:item><name>Steven Marston</name><affiliations><json:string>National Heart and Lung Institute, Imperial College, SW3 6LY London, UK</json:string></affiliations></json:item><json:item><name>Kathleen M. Trybus</name><affiliations><json:string>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</json:string></affiliations></json:item><json:item><name>Niklas Dahl</name><affiliations><json:string>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</json:string><json:string>E-mail: niklas.dahl@genpat.uu.se</json:string></affiliations></json:item></author><articleId><json:string>ddm302</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. 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(INIST-CNRS)</name></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>2007 The Author(s)</p></availability><date>2007-10-18</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Alpha-cardiac actin mutations produce atrial septal defects</title><author xml:id="author-1"><persName><forename type="first">Hans</forename><surname>Matsson</surname></persName><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation></author><author xml:id="author-2"><persName><forename type="first">Jacqueline</forename><surname>Eason</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-3"><persName><forename type="first">Carol 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type="first">Henrik</forename><surname>Enell</surname></persName><affiliation>Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad, Sweden</affiliation></author><author xml:id="author-8"><persName><forename type="first">Anders</forename><surname>Jonzon</surname></persName><affiliation>Childrens Hospital, Uppsala University, S-75185 Uppsala, Sweden</affiliation></author><author xml:id="author-9"><persName><forename type="first">Miikka</forename><surname>Vikkula</surname></persName><affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</affiliation></author><author xml:id="author-10"><persName><forename type="first">Ilse</forename><surname>Gutierrez</surname></persName><affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</affiliation></author><author xml:id="author-11"><persName><forename type="first">Javier</forename><surname>Granados-Riveron</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-12"><persName><forename type="first">Mark</forename><surname>Pope</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-13"><persName><forename type="first">Frances</forename><surname>BuLock</surname></persName><affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</affiliation></author><author xml:id="author-14"><persName><forename type="first">Jane</forename><surname>Cox</surname></persName><affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</affiliation></author><author xml:id="author-15"><persName><forename type="first">Thelma E</forename><surname>Robinson</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-16"><persName><forename type="first">Feifei</forename><surname>Song</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-17"><persName><forename type="first">David J</forename><surname>Brook</surname></persName><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation></author><author xml:id="author-18"><persName><forename type="first">Steven</forename><surname>Marston</surname></persName><affiliation>National Heart and Lung Institute, Imperial College, SW3 6LY London, UK</affiliation></author><author xml:id="author-19"><persName><forename type="first">Kathleen M.</forename><surname>Trybus</surname></persName><affiliation>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</affiliation></author><author xml:id="author-20"><persName><forename type="first">Niklas</forename><surname>Dahl</surname></persName><email>niklas.dahl@genpat.uu.se</email><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-01-15"></date><biblScope unit="volume">17</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="256">256</biblScope><biblScope unit="page" to="265">265</biblScope></imprint></monogr><idno type="istex">5E2AE62A40723AD75DBFD4902D07A47F264FC6F1</idno><idno type="DOI">10.1093/hmg/ddm302</idno><idno type="ArticleID">ddm302</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007-10-18</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of ACTC1 revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in ACTC1 predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.</p></abstract></profileDesc><revisionDesc><change when="2007-10-18">Created</change><change when="2008-01-15">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/5E2AE62A40723AD75DBFD4902D07A47F264FC6F1/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddm302</article-id><article-id pub-id-type="publisher-id">ddm302</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Alpha-cardiac actin mutations produce atrial septal defects</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Matsson</surname><given-names>Hans</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Eason</surname><given-names>Jacqueline</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bookwalter</surname><given-names>Carol S.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Klar</surname><given-names>Joakim</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gustavsson</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sunnegårdh</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Enell</surname><given-names>Henrik</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Jonzon</surname><given-names>Anders</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Vikkula</surname><given-names>Miikka</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Gutierrez</surname><given-names>Ilse</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Granados-Riveron</surname><given-names>Javier</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Pope</surname><given-names>Mark</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bu’Lock</surname><given-names>Frances</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Cox</surname><given-names>Jane</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Robinson</surname><given-names>Thelma E</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>Feifei</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Brook</surname><given-names>David J</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Marston</surname><given-names>Steven</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Trybus</surname><given-names>Kathleen M.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Dahl</surname><given-names>Niklas</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Genetics and Pathology, The Rudbeck Laboratory</addr-line>, <institution>Uppsala University and University Hospital</institution>, <addr-line>S-75185 Uppsala</addr-line>, <country>Sweden</country></aff><aff id="af2"><label>2</label><addr-line>Institute of Genetics</addr-line>, <institution>University of Nottingham, Queen’s Medical Centre</institution>, <addr-line>NG7 2UH Nottingham</addr-line>, <country>UK</country></aff><aff id="af3"><label>3</label><addr-line>Department of Molecular Physiology and Biophysics</addr-line>, <institution>University of Vermont</institution>, <addr-line>VT 05405 Burlington</addr-line>, <country>USA</country></aff><aff id="af4"><label>4</label><institution>The Queen Silvia Children’s Hospital</institution>, <addr-line>S-416 85 Göteborg</addr-line>, <country>Sweden</country></aff><aff id="af5"><label>5</label><addr-line>Department of Pedriatics</addr-line>, <institution>County Hospital of Halmstad</institution>, <addr-line>S-301 85 Halmstad</addr-line>, <country>Sweden</country></aff><aff id="af6"><label>6</label><addr-line>Children’s Hospital</addr-line>, <institution>Uppsala University</institution>, <addr-line>S-75185 Uppsala</addr-line>, <country>Sweden</country></aff><aff id="af7"><label>7</label><addr-line>Human Molecular Genetics (GEHU), Christian de Duve Institute</addr-line>, <institution>Université catholique de Louvain</institution>, <addr-line>B-1200 Brussels</addr-line>, <country>Belgium</country></aff><aff id="af8"><label>8</label><addr-line>Department of Pediatric Cardiology</addr-line>, <institution>Glenfield Hospital</institution>, <addr-line>LE3 9QP Leicester</addr-line>, <country>UK</country></aff><aff id="af9"><label>9</label><institution>National Heart and Lung Institute, Imperial College</institution>, <addr-line>SW3 6LY London</addr-line>, <country>UK</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Department of Genetics and Pathology</addr-line>, <institution>The Rudbeck Laboratory, Uppsala University</institution>, <addr-line>751 85 Uppsala</addr-line>, <country>Sweden</country>. Tel: <phone>+46 18 611 2799</phone>; Fax: <fax>+46 18 554025</fax>; Email: <email>niklas.dahl@genpat.uu.se</email></corresp></author-notes><pub-date pub-type="ppub"><day>15</day><month>1</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>18</day><month>10</month><year>2007</year></pub-date><volume>17</volume><issue>2</issue><fpage>256</fpage><lpage>265</lpage><history><date date-type="received"><day>28</day><month>8</month><year>2007</year></date><date date-type="accepted"><day>10</day><month>10</month><year>2007</year></date></history><copyright-statement>© 2007 The Author(s)</copyright-statement><copyright-year>2008</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license><abstract><p>Atrial septal defect (ASD) is one of the most frequent congenital heart defects (CHDs) with a variable phenotypic effect depending on the size of the septal shunt. We identified two pedigrees comprising 20 members segregating isolated autosomal dominant secundum ASD. By genetic mapping, we identified the gene-encoding alpha-cardiac actin (ACTC1), which is essential for cardiac contraction, as the likely candidate. A mutation screen of the coding regions of <italic>ACTC1</italic> revealed a founder mutation predicting an M123V substitution in affected individuals of both pedigrees. Functional analysis of ACTC1 with an M123V substitution shows a reduced affinity for myosin, but with retained actomyosin motor properties. We also screened 408 sporadic patients with CHDs and identified a case with ASD and a 17-bp deletion in <italic>ACTC1</italic> predicting a non-functional protein. Morpholino (MO) knockdown of ACTC1 in chick embryos produces delayed looping and reduced atrial septa, supporting a developmental role for this protein. The combined results indicate, for the first time, that ACTC1 mutations or reduced ACTC1 levels may lead to ASD without signs of cardiomyopathy.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Alpha-cardiac actin mutations produce atrial septal defects</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Alpha-cardiac actin mutations produce atrial septal defects</title></titleInfo><name type="personal"><namePart type="given">Hans</namePart><namePart type="family">Matsson</namePart><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jacqueline</namePart><namePart type="family">Eason</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Carol S.</namePart><namePart type="family">Bookwalter</namePart><affiliation>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joakim</namePart><namePart type="family">Klar</namePart><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Gustavsson</namePart><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan</namePart><namePart type="family">Sunnegrdh</namePart><affiliation>The Queen Silvia Childrens Hospital, S-416 85 Gteborg, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Henrik</namePart><namePart type="family">Enell</namePart><affiliation>Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anders</namePart><namePart type="family">Jonzon</namePart><affiliation>Childrens Hospital, Uppsala University, S-75185 Uppsala, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Miikka</namePart><namePart type="family">Vikkula</namePart><affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ilse</namePart><namePart type="family">Gutierrez</namePart><affiliation>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Javier</namePart><namePart type="family">Granados-Riveron</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark</namePart><namePart type="family">Pope</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Frances</namePart><namePart type="family">BuLock</namePart><affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jane</namePart><namePart type="family">Cox</namePart><affiliation>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thelma E</namePart><namePart type="family">Robinson</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Feifei</namePart><namePart type="family">Song</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David J</namePart><namePart type="family">Brook</namePart><affiliation>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steven</namePart><namePart type="family">Marston</namePart><affiliation>National Heart and Lung Institute, Imperial College, SW3 6LY London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kathleen M.</namePart><namePart type="family">Trybus</namePart><affiliation>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Niklas</namePart><namePart type="family">Dahl</namePart><affiliation>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala, Sweden</affiliation><affiliation>E-mail: niklas.dahl@genpat.uu.se</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2008-01-15</dateIssued><dateCreated encoding="w3cdtf">2007-10-18</dateCreated><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Atrial septal defect (ASD) is one of the 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