Please use this identifier to cite or link to this item:
Title: Autism with seizures and intellectual disability : possible causative role of gain-of-function of the inwardly-rectifying K + channel Kir4.1
Authors: Sicca, Federico
Imbrici, Paola
D'Adamo, Maria Cristina
Moro, Francesca
Bonatti, Fabrizia
Brovedani, Paola
Grottesi, Alessandro
Guerrini, Renzo
Masi, Gabriele
Santorelli, Filippo Maria
Pessia, Mauro
Keywords: Autism -- Diagnosis
Epilepsy -- Diagnosis
Mental fatigue
Mental retardation
Potassium channels
Autism in adolescence
Epilepsy in adolescence
Issue Date: 2011
Publisher: Elsevier Inc.
Citation: Sicca, F., Imbrici, P., D'Adamo, M. C., Moro, F., Bonatti, F., Brovedani, P.,... Pessia, M. (2011). Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K + channel Kir4.1. Neurobiology of Disease, 43(1), 239-247.
Abstract: The inwardly-rectifying potassium channel Kir4.1 is a major player in the astrocyte-mediated regulation of [K +] o in the brain, which is essential for normal neuronal activity and synaptic functioning. KCNJ10, encoding Kir4.1, has been recently linked to seizure susceptibility in humans and mice, and is a possible candidate gene for Autism Spectrum Disorders (ASD). In this study, we performed a mutational screening of KCNJ10 in 52 patients with epilepsy of "unknown cause" associated with impairment of either cognitive or communicative abilities, or both. Among them, 14 patients fitted the diagnostic criteria for ASD. We identified two heterozygous KCNJ10 mutations (p.R18Q and p.V84M) in three children (two unrelated families) with seizures, ASD, and intellectual disability. The mutations replaced amino acid residues that are highly conserved throughout evolution and were undetected in about 500 healthy chromosomes. The effects of mutations on channel activity were functionally assayed using a heterologous expression system. These studies indicated that the molecular mechanism contributing to the disorder relates to an increase in either surface-expression or conductance of the Kir4.1 channel. Unlike previous syndromic associations of genetic variants in KCNJ10, the pure neuropsychiatric phenotype in our patients suggests that the new mutations affect K + homeostasis mainly in the brain, by acting through gain-of-function defects. Dysfunction in astrocytic-dependent K + buffering may contribute to autism/epilepsy phenotype, by altering neuronal excitability and synaptic function, and may represent a new target for novel therapeutic approaches.
Appears in Collections:Scholarly Works - FacM&SPB

Files in This Item:
File Description SizeFormat 
  Restricted Access
1.27 MBAdobe PDFView/Open Request a copy

Items in OAR@UM are protected by copyright, with all rights reserved, unless otherwise indicated.