Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy.
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.
Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.|Molecular Medicine Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Federico
F
Sicca
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
Elena
E
Ambrosini
Molecular Medicine Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Maria
M
Marchese
School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.
Luigi
L
Sforna
School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.
Ilenio
I
Servettini
Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Giulia
G
Valvo
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
Maria Stefania
MS
Brignone
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
Angela
A
Lanciotti
Molecular Medicine Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Francesca
F
Moro
SuperComputing Applications and Innovation-CINECA, Via dei Tizii, 6, 00185-Roma, Italy.
Alessandro
A
Grottesi
Department of Chemistry, Biology and Biotechnology, University of Perugia, Piazzale Gambuli, 06132-Perugia, Italy.
Luigi
L
Catacuzzeno
Clinical Neurophysiology Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Sara
S
Baldini
School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.
Sonia
S
Hasan
School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.|Faculty of Medicine, Department of Physiology &Biochemistry, University of Malta, MSD 2080-Msida, Malta.
Maria Cristina
MC
D'Adamo
Department of Chemistry, Biology and Biotechnology, University of Perugia, Piazzale Gambuli, 06132-Perugia, Italy.
Fabio
F
Franciolini
Department of Pharmacology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161-Rome, Italy.
Paola
P
Molinari
Molecular Medicine Laboratory, Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Via dei Giacinti 2, 56128-Pisa, Italy.
Filippo M
FM
Santorelli
School of Medicine, Section of Physiology &Biochemistry, Department of Experimental Medicine, Piazzale Gambuli, University of Perugia, 06132-Perugia, Italy.|Faculty of Medicine, Department of Physiology &Biochemistry, University of Malta, MSD 2080-Msida, Malta.
Mauro
M
Pessia
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