Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.
Identifieur interne : 002F86 ( Main/Exploration ); précédent : 002F85; suivant : 002F87Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.
Auteurs : Minaka Ishibashi [Australie] ; Elizabeth Manning [Australie] ; Cheryl Shoubridge [Australie] ; Monika Krecsmarik [France] ; Thomas A. Hawkins [Royaume-Uni] ; Jean Giacomotto [Australie] ; Ting Zhao [Australie] ; Thomas Mueller [États-Unis] ; Patricia I. Bader [États-Unis] ; Sau W. Cheung [États-Unis] ; Pawel Stankiewicz [États-Unis] ; Nicole L. Bain [Australie] ; Anna Hackett [Australie] ; Chilamakuri C S. Reddy [Norvège] ; Alejandro S. Mechaly [Australie] ; Bernard Peers [Belgique] ; Stephen W. Wilson [Royaume-Uni] ; Boris Lenhard [Norvège] ; Laure Bally-Cuif [France] ; Jozef Gecz [Australie] ; Thomas S. Becker [Australie] ; Silke Rinkwitz [Australie]Source :
- Human genetics [ 1432-1203 ] ; 2015.
Descripteurs français
- KwdFr :
- Adulte, Animal génétiquement modifié, Animaux, Danio zébré, Dosage génique, Duplication de gène, Déficience intellectuelle (génétique), Embryon non mammalien, Encéphale (embryologie), Encéphale (métabolisme), Facteurs de transcription (génétique), Facteurs de transcription (métabolisme), Femelle, Humains, Mâle, Protéines à homéodomaine (génétique), Protéines à homéodomaine (métabolisme), Régulation de l'expression des gènes au cours du développement, Variations de nombre de copies de segment d'ADN, Études cas-témoins.
- MESH :
- embryologie : Encéphale.
- génétique : Déficience intellectuelle, Facteurs de transcription, Protéines à homéodomaine.
- métabolisme : Encéphale, Facteurs de transcription, Protéines à homéodomaine.
- Adulte, Animal génétiquement modifié, Animaux, Danio zébré, Dosage génique, Duplication de gène, Embryon non mammalien, Femelle, Humains, Mâle, Régulation de l'expression des gènes au cours du développement, Variations de nombre de copies de segment d'ADN, Études cas-témoins.
English descriptors
- KwdEn :
- Adult, Animals, Animals, Genetically Modified, Brain (embryology), Brain (metabolism), Case-Control Studies, DNA Copy Number Variations, Embryo, Nonmammalian, Female, Gene Dosage, Gene Duplication, Gene Expression Regulation, Developmental, Homeodomain Proteins (genetics), Homeodomain Proteins (metabolism), Humans, Intellectual Disability (genetics), Male, Transcription Factors (genetics), Transcription Factors (metabolism), Zebrafish.
- MESH :
- chemical , genetics : Homeodomain Proteins, Transcription Factors.
- embryology : Brain.
- genetics : Intellectual Disability.
- metabolism : Brain, Homeodomain Proteins, Transcription Factors.
- Adult, Animals, Animals, Genetically Modified, Case-Control Studies, DNA Copy Number Variations, Embryo, Nonmammalian, Female, Gene Dosage, Gene Duplication, Gene Expression Regulation, Developmental, Humans, Male, Zebrafish.
Abstract
Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.
DOI: 10.1007/s00439-015-1594-x
PubMed: 26337422
Affiliations:
- Australie, Belgique, France, Norvège, Royaume-Uni, États-Unis
- Indiana, Nouvelle-Galles du Sud, Province de Liège, Région wallonne, Texas
- Houston, Liège, Sydney
- Université de Liège, Université de Sydney
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Le document en format XML
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Hawkins</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT</wicri:regionArea><wicri:noRegion>WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Giacomotto, Jean" sort="Giacomotto, Jean" uniqKey="Giacomotto J" first="Jean" last="Giacomotto">Jean Giacomotto</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Zhao, Ting" sort="Zhao, Ting" uniqKey="Zhao T" first="Ting" last="Zhao">Ting Zhao</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Mueller, Thomas" sort="Mueller, Thomas" uniqKey="Mueller T" first="Thomas" last="Mueller">Thomas Mueller</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biology, Kansas State University, Manhattan, KS, 66502, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biology, Kansas State University, Manhattan, KS, 66502</wicri:regionArea><wicri:noRegion>66502</wicri:noRegion></affiliation></author><author><name sortKey="Bader, Patricia I" sort="Bader, Patricia I" uniqKey="Bader P" first="Patricia I" last="Bader">Patricia I. Bader</name><affiliation wicri:level="2"><nlm:affiliation>Parkview Cytogenetics and Northeast Indiana Genetics, Fort Wayne, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Parkview Cytogenetics and Northeast Indiana Genetics, Fort Wayne, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Cheung, Sau W" sort="Cheung, Sau W" uniqKey="Cheung S" first="Sau W" last="Cheung">Sau W. Cheung</name><affiliation wicri:level="3"><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston</wicri:regionArea><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name><affiliation wicri:level="3"><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston</wicri:regionArea><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Bain, Nicole L" sort="Bain, Nicole L" uniqKey="Bain N" first="Nicole L" last="Bain">Nicole L. Bain</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305</wicri:regionArea><wicri:noRegion>2305</wicri:noRegion></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation wicri:level="1"><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, John Hunter Hospital, Newcastle, NSW, 2305, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, John Hunter Hospital, Newcastle, NSW, 2305</wicri:regionArea><wicri:noRegion>2305</wicri:noRegion></affiliation></author><author><name sortKey="Reddy, Chilamakuri C S" sort="Reddy, Chilamakuri C S" uniqKey="Reddy C" first="Chilamakuri C S" last="Reddy">Chilamakuri C S. Reddy</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Mechaly, Alejandro S" sort="Mechaly, Alejandro S" uniqKey="Mechaly A" first="Alejandro S" last="Mechaly">Alejandro S. 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Wilson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT</wicri:regionArea><wicri:noRegion>WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Lenhard, Boris" sort="Lenhard, Boris" uniqKey="Lenhard B" first="Boris" last="Lenhard">Boris Lenhard</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bally Cuif, Laure" sort="Bally Cuif, Laure" uniqKey="Bally Cuif L" first="Laure" last="Bally-Cuif">Laure Bally-Cuif</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex</wicri:regionArea><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion></affiliation></author><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 Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006</wicri:regionArea><wicri:noRegion>5006</wicri:noRegion></affiliation></author><author><name sortKey="Becker, Thomas S" sort="Becker, Thomas S" uniqKey="Becker T" first="Thomas S" last="Becker">Thomas S. Becker</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Rinkwitz, Silke" sort="Rinkwitz, Silke" uniqKey="Rinkwitz S" first="Silke" last="Rinkwitz">Silke Rinkwitz</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia. silke.rinkwitz@sydney.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26337422</idno><idno type="pmid">26337422</idno><idno type="doi">10.1007/s00439-015-1594-x</idno><idno type="wicri:Area/PubMed/Corpus">002734</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002734</idno><idno type="wicri:Area/PubMed/Curation">002665</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002665</idno><idno 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Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Manning, Elizabeth" sort="Manning, Elizabeth" uniqKey="Manning E" first="Elizabeth" last="Manning">Elizabeth Manning</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name><affiliation wicri:level="1"><nlm:affiliation>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006</wicri:regionArea><wicri:noRegion>5006</wicri:noRegion></affiliation></author><author><name sortKey="Krecsmarik, Monika" sort="Krecsmarik, Monika" uniqKey="Krecsmarik M" first="Monika" last="Krecsmarik">Monika Krecsmarik</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex</wicri:regionArea><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion></affiliation></author><author><name sortKey="Hawkins, Thomas A" sort="Hawkins, Thomas A" uniqKey="Hawkins T" first="Thomas A" last="Hawkins">Thomas A. Hawkins</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT</wicri:regionArea><wicri:noRegion>WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Giacomotto, Jean" sort="Giacomotto, Jean" uniqKey="Giacomotto J" first="Jean" last="Giacomotto">Jean Giacomotto</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Zhao, Ting" sort="Zhao, Ting" uniqKey="Zhao T" first="Ting" last="Zhao">Ting Zhao</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Mueller, Thomas" sort="Mueller, Thomas" uniqKey="Mueller T" first="Thomas" last="Mueller">Thomas Mueller</name><affiliation wicri:level="1"><nlm:affiliation>Division of Biology, Kansas State University, Manhattan, KS, 66502, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Biology, Kansas State University, Manhattan, KS, 66502</wicri:regionArea><wicri:noRegion>66502</wicri:noRegion></affiliation></author><author><name sortKey="Bader, Patricia I" sort="Bader, Patricia I" uniqKey="Bader P" first="Patricia I" last="Bader">Patricia I. Bader</name><affiliation wicri:level="2"><nlm:affiliation>Parkview Cytogenetics and Northeast Indiana Genetics, Fort Wayne, IN, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Parkview Cytogenetics and Northeast Indiana Genetics, Fort Wayne, IN</wicri:regionArea><placeName><region type="state">Indiana</region></placeName></affiliation></author><author><name sortKey="Cheung, Sau W" sort="Cheung, Sau W" uniqKey="Cheung S" first="Sau W" last="Cheung">Sau W. Cheung</name><affiliation wicri:level="3"><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston</wicri:regionArea><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name><affiliation wicri:level="3"><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston</wicri:regionArea><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName></affiliation></author><author><name sortKey="Bain, Nicole L" sort="Bain, Nicole L" uniqKey="Bain N" first="Nicole L" last="Bain">Nicole L. Bain</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305</wicri:regionArea><wicri:noRegion>2305</wicri:noRegion></affiliation></author><author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><affiliation wicri:level="1"><nlm:affiliation>Genetics of Learning Disability Service, Hunter Genetics, John Hunter Hospital, Newcastle, NSW, 2305, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Genetics of Learning Disability Service, Hunter Genetics, John Hunter Hospital, Newcastle, NSW, 2305</wicri:regionArea><wicri:noRegion>2305</wicri:noRegion></affiliation></author><author><name sortKey="Reddy, Chilamakuri C S" sort="Reddy, Chilamakuri C S" uniqKey="Reddy C" first="Chilamakuri C S" last="Reddy">Chilamakuri C S. Reddy</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Mechaly, Alejandro S" sort="Mechaly, Alejandro S" uniqKey="Mechaly A" first="Alejandro S" last="Mechaly">Alejandro S. Mechaly</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Peers, Bernard" sort="Peers, Bernard" uniqKey="Peers B" first="Bernard" last="Peers">Bernard Peers</name><affiliation wicri:level="4"><nlm:affiliation>GIGA Research, Universite de Liege, 4000, Liege, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>GIGA Research, Universite de Liege, 4000, Liege</wicri:regionArea><orgName type="university">Université de Liège</orgName><placeName><settlement type="city">Liège</settlement><region type="region" nuts="1">Région wallonne</region><region type="province" nuts="1">Province de Liège</region></placeName></affiliation></author><author><name sortKey="Wilson, Stephen W" sort="Wilson, Stephen W" uniqKey="Wilson S" first="Stephen W" last="Wilson">Stephen W. Wilson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT</wicri:regionArea><wicri:noRegion>WC1E 6BT</wicri:noRegion></affiliation></author><author><name sortKey="Lenhard, Boris" sort="Lenhard, Boris" uniqKey="Lenhard B" first="Boris" last="Lenhard">Boris Lenhard</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.</nlm:affiliation><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen</wicri:regionArea><wicri:noRegion>Bergen</wicri:noRegion></affiliation></author><author><name sortKey="Bally Cuif, Laure" sort="Bally Cuif, Laure" uniqKey="Bally Cuif L" first="Laure" last="Bally-Cuif">Laure Bally-Cuif</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex</wicri:regionArea><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion><wicri:noRegion>91198, Gif-sur-Yvette Cédex</wicri:noRegion></affiliation></author><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 Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006</wicri:regionArea><wicri:noRegion>5006</wicri:noRegion></affiliation></author><author><name sortKey="Becker, Thomas S" sort="Becker, Thomas S" uniqKey="Becker T" first="Thomas S" last="Becker">Thomas S. Becker</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><author><name sortKey="Rinkwitz, Silke" sort="Rinkwitz, Silke" uniqKey="Rinkwitz S" first="Silke" last="Rinkwitz">Silke Rinkwitz</name><affiliation wicri:level="4"><nlm:affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia. silke.rinkwitz@sydney.edu.au.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author></analytic><series><title level="j">Human genetics</title><idno type="eISSN">1432-1203</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Animals</term><term>Animals, Genetically Modified</term><term>Brain (embryology)</term><term>Brain (metabolism)</term><term>Case-Control Studies</term><term>DNA Copy Number Variations</term><term>Embryo, Nonmammalian</term><term>Female</term><term>Gene Dosage</term><term>Gene Duplication</term><term>Gene Expression Regulation, Developmental</term><term>Homeodomain Proteins (genetics)</term><term>Homeodomain Proteins (metabolism)</term><term>Humans</term><term>Intellectual Disability (genetics)</term><term>Male</term><term>Transcription Factors (genetics)</term><term>Transcription Factors (metabolism)</term><term>Zebrafish</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Animal génétiquement modifié</term><term>Animaux</term><term>Danio zébré</term><term>Dosage génique</term><term>Duplication de gène</term><term>Déficience intellectuelle (génétique)</term><term>Embryon non mammalien</term><term>Encéphale (embryologie)</term><term>Encéphale (métabolisme)</term><term>Facteurs de transcription (génétique)</term><term>Facteurs de transcription (métabolisme)</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Protéines à homéodomaine (génétique)</term><term>Protéines à homéodomaine (métabolisme)</term><term>Régulation de l'expression des gènes au cours du développement</term><term>Variations de nombre de copies de segment d'ADN</term><term>Études cas-témoins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Homeodomain Proteins</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="embryologie" xml:lang="fr"><term>Encéphale</term></keywords><keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Intellectual Disability</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Déficience intellectuelle</term><term>Facteurs de transcription</term><term>Protéines à homéodomaine</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term><term>Homeodomain Proteins</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Encéphale</term><term>Facteurs de transcription</term><term>Protéines à homéodomaine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Animals</term><term>Animals, Genetically Modified</term><term>Case-Control Studies</term><term>DNA Copy Number Variations</term><term>Embryo, Nonmammalian</term><term>Female</term><term>Gene Dosage</term><term>Gene Duplication</term><term>Gene Expression Regulation, Developmental</term><term>Humans</term><term>Male</term><term>Zebrafish</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Animal génétiquement modifié</term><term>Animaux</term><term>Danio zébré</term><term>Dosage génique</term><term>Duplication de gène</term><term>Embryon non mammalien</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Régulation de l'expression des gènes au cours du développement</term><term>Variations de nombre de copies de segment d'ADN</term><term>Études cas-témoins</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>France</li><li>Norvège</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Indiana</li><li>Nouvelle-Galles du Sud</li><li>Province de Liège</li><li>Région wallonne</li><li>Texas</li></region><settlement><li>Houston</li><li>Liège</li><li>Sydney</li></settlement><orgName><li>Université de Liège</li><li>Université de Sydney</li></orgName></list><tree><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Ishibashi, Minaka" sort="Ishibashi, Minaka" uniqKey="Ishibashi M" first="Minaka" last="Ishibashi">Minaka Ishibashi</name></region><name sortKey="Bain, Nicole L" sort="Bain, Nicole L" uniqKey="Bain N" first="Nicole L" last="Bain">Nicole L. Bain</name><name sortKey="Becker, Thomas S" sort="Becker, Thomas S" uniqKey="Becker T" first="Thomas S" last="Becker">Thomas S. Becker</name><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name><name sortKey="Giacomotto, Jean" sort="Giacomotto, Jean" uniqKey="Giacomotto J" first="Jean" last="Giacomotto">Jean Giacomotto</name><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name><name sortKey="Manning, Elizabeth" sort="Manning, Elizabeth" uniqKey="Manning E" first="Elizabeth" last="Manning">Elizabeth Manning</name><name sortKey="Mechaly, Alejandro S" sort="Mechaly, Alejandro S" uniqKey="Mechaly A" first="Alejandro S" last="Mechaly">Alejandro S. Mechaly</name><name sortKey="Rinkwitz, Silke" sort="Rinkwitz, Silke" uniqKey="Rinkwitz S" first="Silke" last="Rinkwitz">Silke Rinkwitz</name><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name><name sortKey="Zhao, Ting" sort="Zhao, Ting" uniqKey="Zhao T" first="Ting" last="Zhao">Ting Zhao</name></country><country name="France"><noRegion><name sortKey="Krecsmarik, Monika" sort="Krecsmarik, Monika" uniqKey="Krecsmarik M" first="Monika" last="Krecsmarik">Monika Krecsmarik</name></noRegion><name sortKey="Bally Cuif, Laure" sort="Bally Cuif, Laure" uniqKey="Bally Cuif L" first="Laure" last="Bally-Cuif">Laure Bally-Cuif</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Hawkins, Thomas A" sort="Hawkins, Thomas A" uniqKey="Hawkins T" first="Thomas A" last="Hawkins">Thomas A. Hawkins</name></noRegion><name sortKey="Wilson, Stephen W" sort="Wilson, Stephen W" uniqKey="Wilson S" first="Stephen W" last="Wilson">Stephen W. Wilson</name></country><country name="États-Unis"><noRegion><name sortKey="Mueller, Thomas" sort="Mueller, Thomas" uniqKey="Mueller T" first="Thomas" last="Mueller">Thomas Mueller</name></noRegion><name sortKey="Bader, Patricia I" sort="Bader, Patricia I" uniqKey="Bader P" first="Patricia I" last="Bader">Patricia I. Bader</name><name sortKey="Cheung, Sau W" sort="Cheung, Sau W" uniqKey="Cheung S" first="Sau W" last="Cheung">Sau W. Cheung</name><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name></country><country name="Norvège"><noRegion><name sortKey="Reddy, Chilamakuri C S" sort="Reddy, Chilamakuri C S" uniqKey="Reddy C" first="Chilamakuri C S" last="Reddy">Chilamakuri C S. Reddy</name></noRegion><name sortKey="Lenhard, Boris" sort="Lenhard, Boris" uniqKey="Lenhard B" first="Boris" last="Lenhard">Boris Lenhard</name></country><country name="Belgique"><region name="Région wallonne"><name sortKey="Peers, Bernard" sort="Peers, Bernard" uniqKey="Peers B" first="Bernard" last="Peers">Bernard Peers</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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