Autism-associated mutations in Kv7 channels induce gating pore current

Autism spectrum disorder (ASD) adversely impacts >1% of children in the United States, 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 that alter arginine gating charges in the voltage sensor of the voltage-gated potassium (K-v) channel K(v)7 (KCNQ) are among those frequently associated with ASD. We hypothesized that these gating charge mutations would induce gating pore current (also termed omega-current) by causing an ionic leak through the mutant voltage sensor. Unexpectedly, we found that wild-type K(v)7 conducts outward gating pore current through its native voltage sensor at positive membrane potentials, owing to a glutamine in the third gating charge position. In bacterial and human K(v)7 channels, gating charge mutations at the R1 and R2 positions cause inward gating pore current through the resting voltage sensor at negative membrane potentials, whereas mutation at R4 causes outward gating pore current through the activated voltage sensor at positive potentials. Remarkably, expression of the K(v)7.3/R2C ASD-associated mutation in vivo in midbrain dopamine neurons of mice disrupts action potential generation and repetitive firing. Overall, our results reveal native and mutant gating pore current in K(v)7 channels and implicate altered control of action potential generation by gating pore current through mutant K(v)7 channels as a potential pathogenic mechanism in autism.

Automated summary

Autism spectrum disorder affects over 1% of children in the United States, resulting in social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis through genome sequencing has identified over 500 genes with mutations in ASD, suggesting that altered control of action potential generation by gating pore current through mutant K(v)7 channels may be a potential pathogenic mechanism in autism.