Alpha-cardiac actin mutations produce atrial septal defects
Identifieur interne : 001352 ( Main/Exploration ); précédent : 001351; suivant : 001353Alpha-cardiac actin mutations produce atrial septal defects
Auteurs : Hans Matsson [Suède] ; Jacqueline Eason [Royaume-Uni] ; Carol S. Bookwalter [États-Unis] ; Joakim Klar [Suède] ; Peter Gustavsson [Suède] ; Jan Sunnegrdh [Suède] ; Henrik Enell [Suède] ; Anders Jonzon [Suède] ; Miikka Vikkula [Belgique] ; Ilse Gutierrez [Belgique] ; Javier Granados-Riveron [Royaume-Uni] ; Mark Pope [Royaume-Uni] ; Frances Bulock [Royaume-Uni] ; Jane Cox [Royaume-Uni] ; Thelma E. Robinson [Royaume-Uni] ; Feifei Song [Royaume-Uni] ; David J. Brook [Royaume-Uni] ; Steven Marston [Royaume-Uni] ; Kathleen M. Trybus [États-Unis] ; Niklas Dahl [Suède]Source :
- 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.
Url:
DOI: 10.1093/hmg/ddm302
Affiliations:
- Belgique, Royaume-Uni, Suède, États-Unis
- Angleterre, East Middle Sweden, Nottinghamshire, Svealand, Vermont
- Nottingham, Uppsala
- Université d'Uppsala, Université de Nottingham
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Bookwalter</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington</wicri:regionArea><placeName><region type="state">Vermont</region></placeName></affiliation></author><author><name sortKey="Klar, Joakim" sort="Klar, Joakim" uniqKey="Klar J" first="Joakim" last="Klar">Joakim Klar</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala</wicri:regionArea><wicri:noRegion>S-75185 Uppsala</wicri:noRegion></affiliation></author><author><name sortKey="Gustavsson, Peter" sort="Gustavsson, Peter" uniqKey="Gustavsson P" first="Peter" last="Gustavsson">Peter Gustavsson</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala</wicri:regionArea><wicri:noRegion>S-75185 Uppsala</wicri:noRegion></affiliation></author><author><name sortKey="Sunnegrdh, Jan" sort="Sunnegrdh, Jan" uniqKey="Sunnegrdh J" first="Jan" last="Sunnegrdh">Jan Sunnegrdh</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>The Queen Silvia Childrens Hospital, S-416 85 Gteborg</wicri:regionArea><wicri:noRegion>S-416 85 Gteborg</wicri:noRegion></affiliation></author><author><name sortKey="Enell, Henrik" sort="Enell, Henrik" uniqKey="Enell H" first="Henrik" last="Enell">Henrik Enell</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Pedriatics, County Hospital of Halmstad, S-301 85 Halmstad</wicri:regionArea><wicri:noRegion>S-301 85 Halmstad</wicri:noRegion></affiliation></author><author><name sortKey="Jonzon, Anders" sort="Jonzon, Anders" uniqKey="Jonzon A" first="Anders" last="Jonzon">Anders Jonzon</name><affiliation wicri:level="4"><country xml:lang="fr">Suède</country><wicri:regionArea>Childrens Hospital, Uppsala University, S-75185 Uppsala</wicri:regionArea><orgName type="university">Université d'Uppsala</orgName><placeName><settlement type="city">Uppsala</settlement><region nuts="1">Svealand</region><region nuts="1">East Middle Sweden</region></placeName></affiliation></author><author><name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels</wicri:regionArea><wicri:noRegion>B-1200 Brussels</wicri:noRegion></affiliation></author><author><name sortKey="Gutierrez, Ilse" sort="Gutierrez, Ilse" uniqKey="Gutierrez I" first="Ilse" last="Gutierrez">Ilse Gutierrez</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Human Molecular Genetics (GEHU), Christian de Duve Institute, Universit catholique de Louvain, B-1200 Brussels</wicri:regionArea><wicri:noRegion>B-1200 Brussels</wicri:noRegion></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 wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham</wicri:regionArea><orgName type="university">Université de Nottingham</orgName><placeName><settlement type="city">Nottingham</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Nottinghamshire</region></placeName></affiliation></author><author><name sortKey="Pope, Mark" sort="Pope, Mark" uniqKey="Pope M" first="Mark" last="Pope">Mark Pope</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham</wicri:regionArea><orgName type="university">Université de Nottingham</orgName><placeName><settlement type="city">Nottingham</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Nottinghamshire</region></placeName></affiliation></author><author><name sortKey="Bulock, Frances" sort="Bulock, Frances" uniqKey="Bulock F" first="Frances" last="Bulock">Frances Bulock</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester</wicri:regionArea><wicri:noRegion>LE3 9QP Leicester</wicri:noRegion></affiliation></author><author><name sortKey="Cox, Jane" sort="Cox, Jane" uniqKey="Cox J" first="Jane" last="Cox">Jane Cox</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Pediatric Cardiology, Glenfield Hospital, LE3 9QP Leicester</wicri:regionArea><wicri:noRegion>LE3 9QP Leicester</wicri:noRegion></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 wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham</wicri:regionArea><orgName type="university">Université de Nottingham</orgName><placeName><settlement type="city">Nottingham</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Nottinghamshire</region></placeName></affiliation></author><author><name sortKey="Song, Feifei" sort="Song, Feifei" uniqKey="Song F" first="Feifei" last="Song">Feifei Song</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham</wicri:regionArea><orgName type="university">Université de Nottingham</orgName><placeName><settlement type="city">Nottingham</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Nottinghamshire</region></placeName></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 wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics, University of Nottingham, Queens Medical Centre, NG7 2UH Nottingham</wicri:regionArea><orgName type="university">Université de Nottingham</orgName><placeName><settlement type="city">Nottingham</settlement><region type="nation">Angleterre</region><region type="région" nuts="1">Nottinghamshire</region></placeName></affiliation></author><author><name sortKey="Marston, Steven" sort="Marston, Steven" uniqKey="Marston S" first="Steven" last="Marston">Steven Marston</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>National Heart and Lung Institute, Imperial College, SW3 6LY London</wicri:regionArea><wicri:noRegion>SW3 6LY London</wicri:noRegion></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 wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular Physiology and Biophysics, University of Vermont, VT 05405 Burlington</wicri:regionArea><placeName><region type="state">Vermont</region></placeName></affiliation></author><author><name sortKey="Dahl, Niklas" sort="Dahl, Niklas" uniqKey="Dahl N" first="Niklas" last="Dahl">Niklas Dahl</name><affiliation wicri:level="1"><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University and University Hospital, S-75185 Uppsala</wicri:regionArea><wicri:noRegion>S-75185 Uppsala</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Suède</country></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><affiliations><list><country><li>Belgique</li><li>Royaume-Uni</li><li>Suède</li><li>États-Unis</li></country><region><li>Angleterre</li><li>East Middle Sweden</li><li>Nottinghamshire</li><li>Svealand</li><li>Vermont</li></region><settlement><li>Nottingham</li><li>Uppsala</li></settlement><orgName><li>Université d'Uppsala</li><li>Université de Nottingham</li></orgName></list><tree><country name="Suède"><noRegion><name sortKey="Matsson, Hans" sort="Matsson, Hans" uniqKey="Matsson H" first="Hans" last="Matsson">Hans Matsson</name></noRegion><name sortKey="Dahl, Niklas" sort="Dahl, Niklas" uniqKey="Dahl N" first="Niklas" last="Dahl">Niklas Dahl</name><name sortKey="Dahl, Niklas" sort="Dahl, Niklas" uniqKey="Dahl N" first="Niklas" last="Dahl">Niklas Dahl</name><name sortKey="Enell, Henrik" sort="Enell, Henrik" uniqKey="Enell H" first="Henrik" last="Enell">Henrik Enell</name><name sortKey="Gustavsson, Peter" sort="Gustavsson, Peter" uniqKey="Gustavsson P" first="Peter" last="Gustavsson">Peter Gustavsson</name><name sortKey="Jonzon, Anders" sort="Jonzon, Anders" uniqKey="Jonzon A" first="Anders" last="Jonzon">Anders Jonzon</name><name sortKey="Klar, Joakim" sort="Klar, Joakim" uniqKey="Klar J" first="Joakim" last="Klar">Joakim Klar</name><name sortKey="Sunnegrdh, Jan" sort="Sunnegrdh, Jan" uniqKey="Sunnegrdh J" first="Jan" last="Sunnegrdh">Jan Sunnegrdh</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Eason, Jacqueline" sort="Eason, Jacqueline" uniqKey="Eason J" first="Jacqueline" last="Eason">Jacqueline Eason</name></region><name sortKey="Brook, David J" sort="Brook, David J" uniqKey="Brook D" first="David J" last="Brook">David J. Brook</name><name sortKey="Bulock, Frances" sort="Bulock, Frances" uniqKey="Bulock F" first="Frances" last="Bulock">Frances Bulock</name><name sortKey="Cox, Jane" sort="Cox, Jane" uniqKey="Cox J" first="Jane" last="Cox">Jane Cox</name><name sortKey="Granados Riveron, Javier" sort="Granados Riveron, Javier" uniqKey="Granados Riveron J" first="Javier" last="Granados-Riveron">Javier Granados-Riveron</name><name sortKey="Marston, Steven" sort="Marston, Steven" uniqKey="Marston S" first="Steven" last="Marston">Steven Marston</name><name sortKey="Pope, Mark" sort="Pope, Mark" uniqKey="Pope M" first="Mark" last="Pope">Mark Pope</name><name sortKey="Robinson, Thelma E" sort="Robinson, Thelma E" uniqKey="Robinson T" first="Thelma E" last="Robinson">Thelma E. Robinson</name><name sortKey="Song, Feifei" sort="Song, Feifei" uniqKey="Song F" first="Feifei" last="Song">Feifei Song</name></country><country name="États-Unis"><region name="Vermont"><name sortKey="Bookwalter, Carol S" sort="Bookwalter, Carol S" uniqKey="Bookwalter C" first="Carol S." last="Bookwalter">Carol S. Bookwalter</name></region><name sortKey="Trybus, Kathleen M" sort="Trybus, Kathleen M" uniqKey="Trybus K" first="Kathleen M." last="Trybus">Kathleen M. Trybus</name></country><country name="Belgique"><noRegion><name sortKey="Vikkula, Miikka" sort="Vikkula, Miikka" uniqKey="Vikkula M" first="Miikka" last="Vikkula">Miikka Vikkula</name></noRegion><name sortKey="Gutierrez, Ilse" sort="Gutierrez, Ilse" uniqKey="Gutierrez I" first="Ilse" last="Gutierrez">Ilse Gutierrez</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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