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dc.contributor.authorPoeta, L.en
dc.contributor.authorFusco, F.en
dc.contributor.authorDrongitis, D.en
dc.contributor.authorShoubridge, C.en
dc.contributor.authorManganelli, G.en
dc.contributor.authorFilosa, S.en
dc.contributor.authorPaciolla, M.en
dc.contributor.authorCourtney, M.en
dc.contributor.authorCollombat, P.en
dc.contributor.authorLioi, M.en
dc.contributor.authorGecz, J.en
dc.contributor.authorUrsini, M.en
dc.contributor.authorMiano, M.en
dc.identifier.citationAmerican Journal of Human Genetics, 2013; 92(1):114-125en
dc.description.abstractIntellectual 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.en
dc.description.statementofresponsibilityLoredana Poeta, Francesca Fusco, Denise Drongitis, Cheryl Shoubridge, Genesia Manganelli, Stefania Filosa, Mariateresa Paciolla, Monica Courtney, Patrick Collombat, Maria Brigida Lioi, Jozef Gecz, Matilde Valeria Ursini, and Maria Giuseppina Mianoen
dc.publisherUniv Chicago Pressen
dc.rights© 2013 by The American Society of Human Genetics. All rights reserved.en
dc.subjectAnimals; Mice, Knockout; Humans; Mice; Epilepsy; Mental Retardation, X-Linked; Oxidoreductases, N-Demethylating; Peptides; Homeodomain Proteins; Transcription Factors; Gene Expression Regulation; DNA Repeat Expansion; Child; Histone Demethylasesen
dc.titleA regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARXen
dc.typeJournal articleen
pubs.library.collectionPaediatrics publicationsen
dc.identifier.orcidShoubridge, C. [0000-0002-0157-3084]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

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