TY - JOUR
T1 - Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy
AU - Sicca, Federico
AU - Ambrosini, Elena
AU - Marchese, Maria
AU - Sforna, Luigi
AU - Servettini, Ilenio
AU - Valvo, Giulia
AU - Brignone, Maria Stefania
AU - Lanciotti, Angela
AU - Moro, Francesca
AU - Grottesi, Alessandro
AU - Catacuzzeno, Luigi
AU - Baldini, Sara
AU - Hasan, Sonia
AU - D'adamo, Maria Cristina
AU - Franciolini, Fabio
AU - Molinari, Paola
AU - Santorelli, Filippo M.
AU - Pessia, Mauro
N1 - Funding Information:
This work was supported by Telethon-Italy (http://www.telethon.it/en) [grant GGP11188], and Fondazione Cassa di Risparmio di Lucca [Grant 567-2014] and Perugia [Grant 3116-2016]. We also thank Dr Letizia Pitto for technical and scientific assistance at the Italian National Research Council (NRC)-zebrafish core facility.
Publisher Copyright:
© The Author(s) 2016.
PY - 2016/9/28
Y1 - 2016/9/28
N2 - 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.
AB - 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.
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U2 - 10.1038/srep34325
DO - 10.1038/srep34325
M3 - Article
AN - SCOPUS:84989277428
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 34325
ER -