A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. (Articolo in rivista)

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  • A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1016/j.ajhg.2012.11.008 (literal)
Alternative label
  • Poeta L, Fusco F, Drongitis D, Shoubridge C, Manganelli G, Filosa S, Paciolla M, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV, Miano MG. (2013)
    A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.
    in American journal of human genetics
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Poeta L, Fusco F, Drongitis D, Shoubridge C, Manganelli G, Filosa S, Paciolla M, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV, Miano MG. (literal)
Pagina inizio
  • 114 (literal)
Pagina fine
  • 125 (literal)
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  • 92(1 (literal)
Rivista
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  • PubMe (literal)
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  • Institute of Genetics and Biophysics \"Adriano Buzzati Traverso,\" Consiglio Nazionale delle Ricerche, Naples 80131, Italy University of Basilicata, Potenza 85100, Italy Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5006, Australia Department of Genetics and Molecular Pathology, Adelaide, South Australia 5006, Australia Istituto Di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli 86077, Italy Université Nice Sophia Antipolis, Nice 06108, France Institut National de la Santé et de la Recherche Médicale Unité 1091, Diabetes Genetics Team, Institute of Biology Valrose, Nice 06108, France (literal)
Titolo
  • A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. (literal)
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. (literal)
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