AustralieFrV1, Main, Exploration, bibRecord, 004868

A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX

Identifieur interne : 004868 ( Main/Exploration ); précédent : 004867; suivant : 004869

A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX

Auteurs : Loredana Poeta [Italie] ; Francesca Fusco [Italie] ; Denise Drongitis [Italie] ; Cheryl Shoubridge [Australie] ; Genesia Manganelli [Italie] ; Stefania Filosa [Italie] ; Mariateresa Paciolla [Italie] ; Monica Courtney [France] ; Patrick Collombat [France] ; Maria Brigida Lioi [Italie] ; Jozef Gecz [Australie] ; Matilde Valeria Ursini [Italie] ; Maria Giuseppina Miano [Italie]

Source :

American Journal of Human Genetics [ 0002-9297 ] ; 2013.

RBID : PMC:3542471

Abstract

Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (ARX) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (KDM5C), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased trans-activity and reduced, but not abolished, binding to the KDM5C regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic Kdm5c mRNA downregulation in murine Arx-knockout embryonic and neural stem cells. Such Kdm5c mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of KDM5C expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542471

DOI: 10.1016/j.ajhg.2012.11.008
PubMed: 23246292
PubMed Central: 3542471

Affiliations:

Le document en format XML

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 to the Polyalanine Expansions in ARX</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links <italic>KDM5C</italic>
 to the Polyalanine Expansions in ARX</title>
<author><name sortKey="Poeta, Loredana" sort="Poeta, Loredana" uniqKey="Poeta L" first="Loredana" last="Poeta">Loredana Poeta</name>
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<author><name sortKey="Lioi, Maria Brigida" sort="Lioi, Maria Brigida" uniqKey="Lioi M" first="Maria Brigida" last="Lioi">Maria Brigida Lioi</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>
<affiliation wicri:level="1"><nlm:aff id="aff3">Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006</wicri:regionArea>
<wicri:noRegion>South Australia 5006</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff4">Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006</wicri:regionArea>
<wicri:noRegion>South Australia 5006</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ursini, Matilde Valeria" sort="Ursini, Matilde Valeria" uniqKey="Ursini M" first="Matilde Valeria" last="Ursini">Matilde Valeria Ursini</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131</wicri:regionArea>
<wicri:noRegion>Naples 80131</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Miano, Maria Giuseppina" sort="Miano, Maria Giuseppina" uniqKey="Miano M" first="Maria Giuseppina" last="Miano">Maria Giuseppina Miano</name>
<affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Institute of Genetics and Biophysics “Adriano Buzzati Traverso,” Consiglio Nazionale delle Ricerche, Naples 80131</wicri:regionArea>
<wicri:noRegion>Naples 80131</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">American Journal of Human Genetics</title>
<idno type="ISSN">0002-9297</idno>
<idno type="eISSN">1537-6605</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Intellectual disability (ID) and epilepsy often occur together and have a dramatic impact on the development and quality of life of the affected children. Polyalanine (polyA)-expansion-encoding mutations of aristaless-related homeobox (<italic>ARX</italic>
) cause a spectrum of X-linked ID (XLID) diseases and chronic epilepsy, including infantile spasms. We show that lysine-specific demethylase 5C (<italic>KDM5C</italic>
), a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX through the binding in a conserved noncoding element. We have studied altered ARX carrying various polyA elongations in individuals with XLID and/or epilepsy. The changes in polyA repeats cause hypomorphic ARX alterations, which exhibit a decreased <italic>trans</italic>
-activity and reduced, but not abolished, binding to the <italic>KDM5C</italic>
 regulatory region. The altered functioning of the mutants tested is likely to correlate with the severity of XLID and/or epilepsy. By quantitative RT-PCR, we observed a dramatic <italic>Kdm5c</italic>
 mRNA downregulation in murine <italic>Arx</italic>
-knockout embryonic and neural stem cells. Such <italic>Kdm5c</italic>
 mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation, which inversely correlated with an increase in H3K4me3 signal. We established that ARX polyA alterations damage the regulation of <italic>KDM5C</italic>
 expression, and we propose a potential ARX-dependent path acting via chromatin remodeling.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Italie</li>
</country>
<region><li>Provence-Alpes-Côte d'Azur</li>
</region>
<settlement><li>Nice</li>
</settlement>
<orgName><li>Université Nice Sophia Antipolis</li>
</orgName>
</list>
<tree><country name="Italie"><noRegion><name sortKey="Poeta, Loredana" sort="Poeta, Loredana" uniqKey="Poeta L" first="Loredana" last="Poeta">Loredana Poeta</name>
</noRegion>
<name sortKey="Drongitis, Denise" sort="Drongitis, Denise" uniqKey="Drongitis D" first="Denise" last="Drongitis">Denise Drongitis</name>
<name sortKey="Filosa, Stefania" sort="Filosa, Stefania" uniqKey="Filosa S" first="Stefania" last="Filosa">Stefania Filosa</name>
<name sortKey="Filosa, Stefania" sort="Filosa, Stefania" uniqKey="Filosa S" first="Stefania" last="Filosa">Stefania Filosa</name>
<name sortKey="Fusco, Francesca" sort="Fusco, Francesca" uniqKey="Fusco F" first="Francesca" last="Fusco">Francesca Fusco</name>
<name sortKey="Lioi, Maria Brigida" sort="Lioi, Maria Brigida" uniqKey="Lioi M" first="Maria Brigida" last="Lioi">Maria Brigida Lioi</name>
<name sortKey="Manganelli, Genesia" sort="Manganelli, Genesia" uniqKey="Manganelli G" first="Genesia" last="Manganelli">Genesia Manganelli</name>
<name sortKey="Manganelli, Genesia" sort="Manganelli, Genesia" uniqKey="Manganelli G" first="Genesia" last="Manganelli">Genesia Manganelli</name>
<name sortKey="Miano, Maria Giuseppina" sort="Miano, Maria Giuseppina" uniqKey="Miano M" first="Maria Giuseppina" last="Miano">Maria Giuseppina Miano</name>
<name sortKey="Paciolla, Mariateresa" sort="Paciolla, Mariateresa" uniqKey="Paciolla M" first="Mariateresa" last="Paciolla">Mariateresa Paciolla</name>
<name sortKey="Paciolla, Mariateresa" sort="Paciolla, Mariateresa" uniqKey="Paciolla M" first="Mariateresa" last="Paciolla">Mariateresa Paciolla</name>
<name sortKey="Poeta, Loredana" sort="Poeta, Loredana" uniqKey="Poeta L" first="Loredana" last="Poeta">Loredana Poeta</name>
<name sortKey="Ursini, Matilde Valeria" sort="Ursini, Matilde Valeria" uniqKey="Ursini M" first="Matilde Valeria" last="Ursini">Matilde Valeria Ursini</name>
</country>
<country name="Australie"><noRegion><name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name>
</noRegion>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<name sortKey="Gecz, Jozef" sort="Gecz, Jozef" uniqKey="Gecz J" first="Jozef" last="Gecz">Jozef Gecz</name>
<name sortKey="Shoubridge, Cheryl" sort="Shoubridge, Cheryl" uniqKey="Shoubridge C" first="Cheryl" last="Shoubridge">Cheryl Shoubridge</name>
</country>
<country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Courtney, Monica" sort="Courtney, Monica" uniqKey="Courtney M" first="Monica" last="Courtney">Monica Courtney</name>
</region>
<name sortKey="Collombat, Patrick" sort="Collombat, Patrick" uniqKey="Collombat P" first="Patrick" last="Collombat">Patrick Collombat</name>
<name sortKey="Collombat, Patrick" sort="Collombat, Patrick" uniqKey="Collombat P" first="Patrick" last="Collombat">Patrick Collombat</name>
<name sortKey="Courtney, Monica" sort="Courtney, Monica" uniqKey="Courtney M" first="Monica" last="Courtney">Monica Courtney</name>
</country>
</tree>
</affiliations>
</record>

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

A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX

A Regulatory Path Associated with X-Linked Intellectual Disability and Epilepsy Links KDM5C to the Polyalanine Expansions in ARX

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