A Novel KCNJ2 Mutation Identified in an Autistic Proband Affects the Single Channel Properties of Kir2.1

• Main Authors: Anna Binda, Ilaria Rivolta, Chiara Villa, Elisa Chisci, Massimiliano Beghi, Cesare M. Cornaggia, Roberto Giovannoni, Romina Combi
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-03-01
• Series: Frontiers in Cellular Neuroscience
• Subjects: autism spectrum disorders; KCNJ2; potassium channel; mutation; patch clamp; single channel
• Online Access: http://journal.frontiersin.org/article/10.3389/fncel.2018.00076/full

Inwardly rectifying potassium channels (Kir) have been historically associated to several cardiovascular disorders. In particular, loss-of-function mutations in the Kir2.1 channel have been reported in cases affected by Andersen-Tawil syndrome while gain-of-function mutations in the same channel cause the short QT3 syndrome. Recently, a missense mutation in Kir2.1, as well as mutations in the Kir4.1, were reported to be involved in autism spectrum disorders (ASDs) suggesting a role of potassium channels in these diseases and introducing the idea of the existence of K+ channel ASDs. Here, we report the identification in an Italian affected family of a novel missense mutation (p.Phe58Ser) in the KCNJ2 gene detected in heterozygosity in a proband affected by autism and borderline for short QT syndrome type 3. The mutation is located in the N-terminal region of the gene coding for the Kir2.1 channel and in particular in a very conserved domain. In vitro assays demonstrated that this mutation results in an increase of the channel conductance and in its open probability. This gain-of-function of the protein is consistent with the autistic phenotype, which is normally associated to an altered neuronal excitability.