Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.
Identifieur interne : 002734 ( PubMed/Corpus ); précédent : 002733; suivant : 002735Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.
Auteurs : Minaka Ishibashi ; Elizabeth Manning ; Cheryl Shoubridge ; Monika Krecsmarik ; Thomas A. Hawkins ; Jean Giacomotto ; Ting Zhao ; Thomas Mueller ; Patricia I. Bader ; Sau W. Cheung ; Pawel Stankiewicz ; Nicole L. Bain ; Anna Hackett ; Chilamakuri C S. Reddy ; Alejandro S. Mechaly ; Bernard Peers ; Stephen W. Wilson ; Boris Lenhard ; Laure Bally-Cuif ; Jozef Gecz ; Thomas S. Becker ; Silke RinkwitzSource :
- Human genetics [ 1432-1203 ] ; 2015.
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
Links to Exploration step
pubmed:26337422Le document en format XML
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<author><name sortKey="Krecsmarik, Monika" sort="Krecsmarik, Monika" uniqKey="Krecsmarik M" first="Monika" last="Krecsmarik">Monika Krecsmarik</name>
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<author><name sortKey="Zhao, Ting" sort="Zhao, Ting" uniqKey="Zhao T" first="Ting" last="Zhao">Ting Zhao</name>
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<author><name sortKey="Mueller, Thomas" sort="Mueller, Thomas" uniqKey="Mueller T" first="Thomas" last="Mueller">Thomas Mueller</name>
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<author><name sortKey="Bader, Patricia I" sort="Bader, Patricia I" uniqKey="Bader P" first="Patricia I" last="Bader">Patricia I. Bader</name>
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<author><name sortKey="Cheung, Sau W" sort="Cheung, Sau W" uniqKey="Cheung S" first="Sau W" last="Cheung">Sau W. Cheung</name>
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<author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name>
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<author><name sortKey="Bain, Nicole L" sort="Bain, Nicole L" uniqKey="Bain N" first="Nicole L" last="Bain">Nicole L. Bain</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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<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><nlm:affiliation>Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Mechaly, Alejandro S" sort="Mechaly, Alejandro S" uniqKey="Mechaly A" first="Alejandro S" last="Mechaly">Alejandro S. Mechaly</name>
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<author><name sortKey="Peers, Bernard" sort="Peers, Bernard" uniqKey="Peers B" first="Bernard" last="Peers">Bernard Peers</name>
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<author><name sortKey="Lenhard, Boris" sort="Lenhard, Boris" uniqKey="Lenhard B" first="Boris" last="Lenhard">Boris Lenhard</name>
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<author><name sortKey="Bally Cuif, Laure" sort="Bally Cuif, Laure" uniqKey="Bally Cuif L" first="Laure" last="Bally-Cuif">Laure Bally-Cuif</name>
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<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<affiliation><nlm:affiliation>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.</nlm:affiliation>
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<author><name sortKey="Becker, Thomas S" sort="Becker, Thomas S" uniqKey="Becker T" first="Thomas S" last="Becker">Thomas S. Becker</name>
<affiliation><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>
</affiliation>
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<author><name sortKey="Rinkwitz, Silke" sort="Rinkwitz, Silke" uniqKey="Rinkwitz S" first="Silke" last="Rinkwitz">Silke Rinkwitz</name>
<affiliation><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>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.</title>
<author><name sortKey="Ishibashi, Minaka" sort="Ishibashi, Minaka" uniqKey="Ishibashi M" first="Minaka" last="Ishibashi">Minaka Ishibashi</name>
<affiliation><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>
</affiliation>
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<author><name sortKey="Manning, Elizabeth" sort="Manning, Elizabeth" uniqKey="Manning E" first="Elizabeth" last="Manning">Elizabeth Manning</name>
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<author><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name>
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<author><name sortKey="Krecsmarik, Monika" sort="Krecsmarik, Monika" uniqKey="Krecsmarik M" first="Monika" last="Krecsmarik">Monika Krecsmarik</name>
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</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><nlm:affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Giacomotto, Jean" sort="Giacomotto, Jean" uniqKey="Giacomotto J" first="Jean" last="Giacomotto">Jean Giacomotto</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Zhao, Ting" sort="Zhao, Ting" uniqKey="Zhao T" first="Ting" last="Zhao">Ting Zhao</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Mueller, Thomas" sort="Mueller, Thomas" uniqKey="Mueller T" first="Thomas" last="Mueller">Thomas Mueller</name>
<affiliation><nlm:affiliation>Division of Biology, Kansas State University, Manhattan, KS, 66502, USA.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Bader, Patricia I" sort="Bader, Patricia I" uniqKey="Bader P" first="Patricia I" last="Bader">Patricia I. Bader</name>
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<author><name sortKey="Cheung, Sau W" sort="Cheung, Sau W" uniqKey="Cheung S" first="Sau W" last="Cheung">Sau W. Cheung</name>
<affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Stankiewicz, Pawel" sort="Stankiewicz, Pawel" uniqKey="Stankiewicz P" first="Pawel" last="Stankiewicz">Pawel Stankiewicz</name>
<affiliation><nlm:affiliation>Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.</nlm:affiliation>
</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><nlm:affiliation>Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Hackett, Anna" sort="Hackett, Anna" uniqKey="Hackett A" first="Anna" last="Hackett">Anna Hackett</name>
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</affiliation>
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<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>
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</affiliation>
</author>
<author><name sortKey="Mechaly, Alejandro S" sort="Mechaly, Alejandro S" uniqKey="Mechaly A" first="Alejandro S" last="Mechaly">Alejandro S. Mechaly</name>
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</affiliation>
</author>
<author><name sortKey="Peers, Bernard" sort="Peers, Bernard" uniqKey="Peers B" first="Bernard" last="Peers">Bernard Peers</name>
<affiliation><nlm:affiliation>GIGA Research, Universite de Liege, 4000, Liege, Belgium.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wilson, Stephen W" sort="Wilson, Stephen W" uniqKey="Wilson S" first="Stephen W" last="Wilson">Stephen W. Wilson</name>
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</affiliation>
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<author><name sortKey="Lenhard, Boris" sort="Lenhard, Boris" uniqKey="Lenhard B" first="Boris" last="Lenhard">Boris Lenhard</name>
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</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>
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</affiliation>
</author>
<author><name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
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</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><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>
</affiliation>
</author>
<author><name sortKey="Rinkwitz, Silke" sort="Rinkwitz, Silke" uniqKey="Rinkwitz S" first="Silke" last="Rinkwitz">Silke Rinkwitz</name>
<affiliation><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>
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<term>Brain (metabolism)</term>
<term>Case-Control Studies</term>
<term>DNA Copy Number Variations</term>
<term>Embryo, Nonmammalian</term>
<term>Female</term>
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<term>Humans</term>
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<term>Gene Dosage</term>
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<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>
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<DateCreated><Year>2015</Year>
<Month>11</Month>
<Day>02</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>04</Month>
<Day>12</Day>
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<Month>11</Month>
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<Title>Human genetics</Title>
<ISOAbbreviation>Hum. Genet.</ISOAbbreviation>
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<ArticleTitle>Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.</ArticleTitle>
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<Abstract><AbstractText>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.</AbstractText>
</Abstract>
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<ForeName>Minaka</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Manning</LastName>
<ForeName>Elizabeth</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Shoubridge</LastName>
<ForeName>Cheryl</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Krecsmarik</LastName>
<ForeName>Monika</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hawkins</LastName>
<ForeName>Thomas A</ForeName>
<Initials>TA</Initials>
<AffiliationInfo><Affiliation>Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.</Affiliation>
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