title: A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX.
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.
authors.affiliation: Institute of Genetics and Biophysics Adriano Buzzati Traverso, Consiglio Nazionale delle Ricerche, Naples 80131, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Poeta
authors.forename: Francesca
authors.initials: F
authors.lastname: Fusco
authors.forename: Denise
authors.initials: D
authors.lastname: Drongitis
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.forename: Genesia
authors.initials: G
authors.lastname: Manganelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Filosa
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Paciolla
authors.forename: Monica
authors.initials: M
authors.lastname: Courtney
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
authors.forename: Maria Brigida
authors.initials: MB
authors.lastname: Lioi
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Matilde Valeria
authors.initials: MV
authors.lastname: Ursini
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Miano
mesh_terms: D000818:Animals; D002648:Child; D042622:DNA Repeat Expansion; D004827:Epilepsy / Q000235:genetics*; D005786:Gene Expression Regulation; D056466:Histone Demethylases; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine; D056466:Histone Demethylases; C086877:KDM5C protein, human; D010089:Oxidoreductases, N-Demethylating