title: Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K+ channel Kir4.1.
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.
authors: Epilepsy, Neurophysiology and Neurogenetics Unit, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Calambrone, Pisa, Italy. federico.sicca@inpe.unipi.it
authors: Federico
authors: F
authors: Sicca
authors: Paola
authors: P
authors: Imbrici
authors: Maria Cristina
authors: MC
authors: D'Adamo
authors: Francesca
authors: F
authors: Moro
authors: Fabrizia
authors: F
authors: Bonatti
authors: Paola
authors: P
authors: Brovedani
authors: Alessandro
authors: A
authors: Grottesi
authors: Renzo
authors: R
authors: Guerrini
authors: Gabriele
authors: G
authors: Masi
authors: Filippo Maria
authors: FM
authors: Santorelli
authors: Mauro
authors: M
authors: Pessia
mesh_terms: D000293:Adolescent; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D055815:Young Adult; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying