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A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.
Poeta, Loredana; Fusco, Francesca; Drongitis, Denise; Shoubridge, Cheryl; Manganelli, Genesia; Filosa, Stefania; Paciolla, Mariateresa; Courtney, Monica; Collombat, Patrick; Lioi, Maria Brigida; Gecz, Jozef; Ursini, Matilde Valeria; Miano, Maria Giuseppina.
Afiliação
  • Poeta L; Institute of Genetics and Biophysics Adriano Buzzati Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy.
Am J Hum Genet ; 92(1): 114-25, 2013 Jan 10.
Article em En | MEDLINE | ID: mdl-23246292
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Fatores de Transcrição / Regulação da Expressão Gênica / Proteínas de Homeodomínio / Deficiência Intelectual Ligada ao Cromossomo X / Epilepsia Tipo de estudo: Risk_factors_studies Limite: Animals / Child / Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Fatores de Transcrição / Regulação da Expressão Gênica / Proteínas de Homeodomínio / Deficiência Intelectual Ligada ao Cromossomo X / Epilepsia Tipo de estudo: Risk_factors_studies Limite: Animals / Child / Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2013 Tipo de documento: Article País de afiliação: Itália