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Title: Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy
Authors: Sicca, Federico
Ambrosini, Elena
Marchese, Maria
Sforna, Luigi
Servettini, Ilenio
Valvo, Giulia
Brignone, Maria Stefania
Lanciotti, Angela
Moro, Francesca
Grottesi, Alessandro
Catacuzzeno, Luigi
Baldini, Sara
Hasan, Sonia M.
D'Adamo, Maria Cristina
Franciolini, Fabio
Molinari, Paola
Santorelli, Filippo Maria
Pessia, Mauro
Keywords: Autistic children
Autism in children
Autism in children -- Diagnosis
Epilepsy in children
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Sicca, F., Ambrosini, E., Marchese, M., Sforna, L., Servettini, I., Valvo, G.,...Pessia, M. (2016). Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy. Scientific Reports, 6, 34325.
Abstract: Dysfunction of the inwardly-rectifying potassium channels Kir4.1 (KCNJ10) represents a pathogenic mechanism contributing to Autism-Epilepsy comorbidity. To define the role of Kir4.1 variants in the disorder, we sequenced KCNJ10 in a sample of affected individuals, and performed genotype-phenotype correlations. The effects of mutations on channel activity, protein trafficking, and astrocyte function were investigated in Xenopus laevis oocytes, and in human astrocytoma cell lines. An in vivo model of the disorder was also explored through generation of kcnj10a morphant zebrafish overexpressing the mutated human KCNJ10. We detected germline heterozygous KCNJ10 variants in 19/175 affected children. Epileptic spasms with dysregulated sensory processing represented the main disease phenotype. When investigated on astrocyte-like cells, the p.R18Q mutation exerted a gain-of-function effect by enhancing Kir4.1 membrane expression and current density. Similarly, the p.R348H variant led to gain of channel function through hindrance of pH-dependent current inhibition. The frequent polymorphism p.R271C seemed, instead, to have no obvious functional effects. Our results confirm that variants in KCNJ10 deserve attention in autism-epilepsy, and provide insight into the molecular mechanisms of autism and seizures. Similar to neurons, astrocyte dysfunction may result in abnormal synaptic transmission and electrical discharge, and should be regarded as a possible pharmacological target in autism-epilepsy. Supplementary information accompanies this paper in the files section.
Appears in Collections:Scholarly Works - FacM&SPB

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