Autism-associated mutations in K <sub>V</sub> 7 channels induce gating pore current
Tamer M. Gamal El-Din, Timothy Lantin, Christopher W. Tschumi, Barbara Juarez, Meagan A. Quinlan, Julia H. Hayano, Jin Li, Larry S. Zweifel, William A. Catterall
Abstract
Significance Autism spectrum disorder (ASD) adversely impacts >1% of children, causing social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis of ASD has advanced dramatically through genome sequencing, which has identified >500 genes with mutations in ASD. Mutations in the voltage sensor of the voltage-gated potassium (K V ) channel K V 7 are frequently associated with ASD. We discovered that these ASD mutations cause an ionic leak through the voltage sensor, termed gating pore current. When these mutations were inserted into the genome of mouse dopamine neurons, they caused a dramatic alteration in the ability of those neurons to fire action potentials in response to electrical stimulation. These changes would impair information processing in neurons, leading to broad changes in brain function.