AustralieFrV1, Main, Exploration, bibRecord, 000861

MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.

Identifieur interne : 000861 ( Main/Exploration ); précédent : 000860; suivant : 000862

MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.

Auteurs : Lise-Marie Donnio [France] ; Baptiste Bidon [France] ; Satoru Hashimoto [France] ; Melanie May [États-Unis] ; Alexey Epanchintsev [France] ; Colm Ryan [France] ; William Allen [États-Unis] ; Anna Hackett [Australie] ; Jozef Gecz [Australie] ; Cindy Skinner [États-Unis] ; Roger E. Stevenson [États-Unis] ; Arjan P M. De Brouwer [Pays-Bas] ; Charles Coutton [France] ; Christine Francannet [France] ; Pierre-Simon Jouk [France] ; Charles E. Schwartz [États-Unis] ; Jean-Marc Egly [France]

Source :

Human molecular genetics [ 1460-2083 ] ; 2017.

RBID : pubmed:28369444

Descripteurs français

English descriptors

KwdEn :
- Abnormalities, Multiple (genetics), Blepharophimosis (genetics), Blepharoptosis (genetics), Gene Expression Regulation (genetics), Genes, Immediate-Early (genetics), Genes, X-Linked (genetics), Heart Defects, Congenital (genetics), Intellectual Disability (genetics), Intellectual Disability (metabolism), Mediator Complex (genetics), Mediator Complex (metabolism), Mental Retardation, X-Linked (genetics), Mutation, Phenotype, Repressor Proteins.
MESH :
- chemical , genetics : Mediator Complex.
- genetics : Abnormalities, Multiple, Blepharophimosis, Blepharoptosis, Gene Expression Regulation, Genes, Immediate-Early, Genes, X-Linked, Heart Defects, Congenital, Intellectual Disability, Mental Retardation, X-Linked.
- metabolism : Intellectual Disability, Mediator Complex.
- Mutation, Phenotype, Repressor Proteins.

Abstract

Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p.R206Q, p.N898D, p.R961W, p.N1007S, p.R1148H, p.S1165P and p.R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p.R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.

DOI: 10.1093/hmg/ddx099
PubMed: 28369444

Affiliations:

Le document en format XML

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<sourceDesc><biblStruct><analytic><title xml:lang="en">MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.</title>
<author><name sortKey="Donnio, Lise Marie" sort="Donnio, Lise Marie" uniqKey="Donnio L" first="Lise-Marie" last="Donnio">Lise-Marie Donnio</name>
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<author><name sortKey="Ryan, Colm" sort="Ryan, Colm" uniqKey="Ryan C" first="Colm" last="Ryan">Colm Ryan</name>
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<author><name sortKey="Allen, William" sort="Allen, William" uniqKey="Allen W" first="William" last="Allen">William Allen</name>
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<author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Hunter Genetics, Waratah, NSW 2298</wicri:regionArea>
<wicri:noRegion>NSW 2298</wicri:noRegion>
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<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<affiliation wicri:level="1"><nlm:affiliation>School of Medicine, and the Robinson Research Institute, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Medicine, and the Robinson Research Institute, The University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, SA 5000</wicri:regionArea>
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<author><name sortKey="Skinner, Cindy" sort="Skinner, Cindy" uniqKey="Skinner C" first="Cindy" last="Skinner">Cindy Skinner</name>
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<author><name sortKey="Stevenson, Roger E" sort="Stevenson, Roger E" uniqKey="Stevenson R" first="Roger E" last="Stevenson">Roger E. Stevenson</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, SC 29649</wicri:regionArea>
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</author>
<author><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P M" last="De Brouwer">Arjan P M. De Brouwer</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525?HP, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525?HP</wicri:regionArea>
<wicri:noRegion>6525?HP</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Coutton, Charles" sort="Coutton, Charles" uniqKey="Coutton C" first="Charles" last="Coutton">Charles Coutton</name>
<affiliation wicri:level="1"><nlm:affiliation>Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble</wicri:regionArea>
<wicri:noRegion>38000 Grenoble</wicri:noRegion>
<placeName><settlement type="city">Grenoble</settlement>
<region type="region" nuts="2">Auvergne-Rhône-Alpes</region>
<region type="old region" nuts="2">Rhône-Alpes</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Francannet, Christine" sort="Francannet, Christine" uniqKey="Francannet C" first="Christine" last="Francannet">Christine Francannet</name>
<affiliation wicri:level="1"><nlm:affiliation>Service de Génétique Médicale, Centre Hospitalier-Universitaire, 63003 Clermont-Ferrand, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Service de Génétique Médicale, Centre Hospitalier-Universitaire, 63003 Clermont-Ferrand</wicri:regionArea>
<wicri:noRegion>63003 Clermont-Ferrand</wicri:noRegion>
<wicri:noRegion>63003 Clermont-Ferrand</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Jouk, Pierre Simon" sort="Jouk, Pierre Simon" uniqKey="Jouk P" first="Pierre-Simon" last="Jouk">Pierre-Simon Jouk</name>
<affiliation wicri:level="1"><nlm:affiliation>Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Département de Génétique et Procréation, Centre Hospitalier-Universitaire, Institut Albert Bonniot, CNRS/INSERM/Université Grenoble Alpes, 38000 Grenoble</wicri:regionArea>
<wicri:noRegion>38000 Grenoble</wicri:noRegion>
<placeName><settlement type="city">Grenoble</settlement>
<region type="region" nuts="2">Auvergne-Rhône-Alpes</region>
<region type="old region" nuts="2">Rhône-Alpes</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E" last="Schwartz">Charles E. Schwartz</name>
<affiliation wicri:level="2"><nlm:affiliation>Greenwood Genetic Center, Greenwood, SC 29649, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Greenwood Genetic Center, Greenwood, SC 29649</wicri:regionArea>
<placeName><region type="state">Caroline du Sud</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Egly, Jean Marc" sort="Egly, Jean Marc" uniqKey="Egly J" first="Jean-Marc" last="Egly">Jean-Marc Egly</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Department of Functional Genomics and Cancer biology, IGBMC, CNRS/INSERM/Université de Strasbourg, 67404 Illkirch-Graffenstaden</wicri:regionArea>
<placeName><region type="region" nuts="2">Grand Est</region>
<region type="old region" nuts="2">Alsace (région administrative)</region>
<settlement type="city">Illkirch-Graffenstaden</settlement>
<settlement type="city">Strasbourg</settlement>
</placeName>
<orgName type="university">Université de Strasbourg</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j">Human molecular genetics</title>
<idno type="eISSN">1460-2083</idno>
<imprint><date when="2017" type="published">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Abnormalities, Multiple (genetics)</term>
<term>Blepharophimosis (genetics)</term>
<term>Blepharoptosis (genetics)</term>
<term>Gene Expression Regulation (genetics)</term>
<term>Genes, Immediate-Early (genetics)</term>
<term>Genes, X-Linked (genetics)</term>
<term>Heart Defects, Congenital (genetics)</term>
<term>Intellectual Disability (genetics)</term>
<term>Intellectual Disability (metabolism)</term>
<term>Mediator Complex (genetics)</term>
<term>Mediator Complex (metabolism)</term>
<term>Mental Retardation, X-Linked (genetics)</term>
<term>Mutation</term>
<term>Phenotype</term>
<term>Repressor Proteins</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Blépharophimosis (génétique)</term>
<term>Blépharoptose (génétique)</term>
<term>Cardiopathies congénitales (génétique)</term>
<term>Complexe médiateur (génétique)</term>
<term>Complexe médiateur (métabolisme)</term>
<term>Déficience intellectuelle (génétique)</term>
<term>Déficience intellectuelle (métabolisme)</term>
<term>Gènes liés au chromosome X (génétique)</term>
<term>Gènes précoces (génétique)</term>
<term>Malformations multiples (génétique)</term>
<term>Mutation</term>
<term>Phénotype</term>
<term>Protéines de répression</term>
<term>Retard mental lié à l'X (génétique)</term>
<term>Régulation de l'expression des gènes (génétique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Mediator Complex</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Abnormalities, Multiple</term>
<term>Blepharophimosis</term>
<term>Blepharoptosis</term>
<term>Gene Expression Regulation</term>
<term>Genes, Immediate-Early</term>
<term>Genes, X-Linked</term>
<term>Heart Defects, Congenital</term>
<term>Intellectual Disability</term>
<term>Mental Retardation, X-Linked</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Blépharophimosis</term>
<term>Blépharoptose</term>
<term>Cardiopathies congénitales</term>
<term>Complexe médiateur</term>
<term>Déficience intellectuelle</term>
<term>Gènes liés au chromosome X</term>
<term>Gènes précoces</term>
<term>Malformations multiples</term>
<term>Retard mental lié à l'X</term>
<term>Régulation de l'expression des gènes</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intellectual Disability</term>
<term>Mediator Complex</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexe médiateur</term>
<term>Déficience intellectuelle</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Mutation</term>
<term>Phenotype</term>
<term>Repressor Proteins</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Mutation</term>
<term>Phénotype</term>
<term>Protéines de répression</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p.R206Q, p.N898D, p.R961W, p.N1007S, p.R1148H, p.S1165P and p.R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p.R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Pays-Bas</li>
<li>États-Unis</li>
</country>
<region><li>Alsace (région administrative)</li>
<li>Auvergne-Rhône-Alpes</li>
<li>Caroline du Nord</li>
<li>Caroline du Sud</li>
<li>Grand Est</li>
<li>Rhône-Alpes</li>
</region>
<settlement><li>Grenoble</li>
<li>Illkirch-Graffenstaden</li>
<li>Strasbourg</li>
</settlement>
<orgName><li>Université de Strasbourg</li>
</orgName>
</list>
<tree><country name="France"><region name="Grand Est"><name sortKey="Donnio, Lise Marie" sort="Donnio, Lise Marie" uniqKey="Donnio L" first="Lise-Marie" last="Donnio">Lise-Marie Donnio</name>
</region>
<name sortKey="Bidon, Baptiste" sort="Bidon, Baptiste" uniqKey="Bidon B" first="Baptiste" last="Bidon">Baptiste Bidon</name>
<name sortKey="Coutton, Charles" sort="Coutton, Charles" uniqKey="Coutton C" first="Charles" last="Coutton">Charles Coutton</name>
<name sortKey="Egly, Jean Marc" sort="Egly, Jean Marc" uniqKey="Egly J" first="Jean-Marc" last="Egly">Jean-Marc Egly</name>
<name sortKey="Epanchintsev, Alexey" sort="Epanchintsev, Alexey" uniqKey="Epanchintsev A" first="Alexey" last="Epanchintsev">Alexey Epanchintsev</name>
<name sortKey="Francannet, Christine" sort="Francannet, Christine" uniqKey="Francannet C" first="Christine" last="Francannet">Christine Francannet</name>
<name sortKey="Hashimoto, Satoru" sort="Hashimoto, Satoru" uniqKey="Hashimoto S" first="Satoru" last="Hashimoto">Satoru Hashimoto</name>
<name sortKey="Jouk, Pierre Simon" sort="Jouk, Pierre Simon" uniqKey="Jouk P" first="Pierre-Simon" last="Jouk">Pierre-Simon Jouk</name>
<name sortKey="Ryan, Colm" sort="Ryan, Colm" uniqKey="Ryan C" first="Colm" last="Ryan">Colm Ryan</name>
</country>
<country name="États-Unis"><region name="Caroline du Sud"><name sortKey="May, Melanie" sort="May, Melanie" uniqKey="May M" first="Melanie" last="May">Melanie May</name>
</region>
<name sortKey="Allen, William" sort="Allen, William" uniqKey="Allen W" first="William" last="Allen">William Allen</name>
<name sortKey="Schwartz, Charles E" sort="Schwartz, Charles E" uniqKey="Schwartz C" first="Charles E" last="Schwartz">Charles E. Schwartz</name>
<name sortKey="Skinner, Cindy" sort="Skinner, Cindy" uniqKey="Skinner C" first="Cindy" last="Skinner">Cindy Skinner</name>
<name sortKey="Stevenson, Roger E" sort="Stevenson, Roger E" uniqKey="Stevenson R" first="Roger E" last="Stevenson">Roger E. Stevenson</name>
</country>
<country name="Australie"><noRegion><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
</noRegion>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
</country>
<country name="Pays-Bas"><noRegion><name sortKey="De Brouwer, Arjan P M" sort="De Brouwer, Arjan P M" uniqKey="De Brouwer A" first="Arjan P M" last="De Brouwer">Arjan P M. De Brouwer</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.

MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.

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	Serveur d'exploration sur les relations entre la France et l'Australie
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