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Sicca F, Ambrosini E, Marchese M, et al. Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy. Sci Rep. 2016;6:34325doi: 10.1038/srep34325.
Sicca, F., Ambrosini, E., Marchese, M., Sforna, L., Servettini, I., Valvo, G., Brignone, M. S., Lanciotti, A., Moro, F., Grottesi, A., Catacuzzeno, L., Baldini, S., Hasan, S., D'Adamo, M. C., Franciolini, F., Molinari, P., Santorelli, F. M., & Pessia, M. (2016). Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy. Scientific reports, 634325. https://doi.org/10.1038/srep34325
Sicca, Federico, et al. "Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy." Scientific reports vol. 6 (2016): 34325. doi: https://doi.org/10.1038/srep34325
Sicca F, Ambrosini E, Marchese M, Sforna L, Servettini I, Valvo G, Brignone MS, Lanciotti A, Moro F, Grottesi A, Catacuzzeno L, Baldini S, Hasan S, D'Adamo MC, Franciolini F, Molinari P, Santorelli FM, Pessia M. Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy. Sci Rep. 2016 Sep 28;6:34325. doi: 10.1038/srep34325. PMID: 27677466; PMCID: PMC5039625.
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Sci Rep. 2016 Sep 28;6:34325. doi: 10.1038/srep34325.

Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy.

Scientific reports

Federico Sicca, Elena Ambrosini, Maria Marchese, Luigi Sforna, Ilenio Servettini, Giulia Valvo, Maria Stefania Brignone, Angela Lanciotti, Francesca Moro, Alessandro Grottesi, Luigi Catacuzzeno, Sara Baldini, Sonia Hasan, Maria Cristina D'Adamo, Fabio Franciolini, Paola Molinari, Filippo M Santorelli, Mauro Pessia

Affiliations

  1. Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
  2. Molecular Medicine Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
  3. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
  4. School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.
  5. SuperComputing Applications and Innovation-CINECA, Via dei Tizii, 6, 00185-Roma, Italy.
  6. Department of Chemistry, Biology and Biotechnology, University of Perugia, Piazzale Gambuli, 06132-Perugia, Italy.
  7. Faculty of Medicine, Department of Physiology &Biochemistry, University of Malta, MSD 2080-Msida, Malta.
  8. Department of Pharmacology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.

PMID: 27677466 PMCID: PMC5039625 DOI: 10.1038/srep34325

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.

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