An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior

by Tyler Buddell, Vladislav Friedman, Cody J. Drozd, Christopher C. Quinn Common and rare variants of theCACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about howCACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rarede novo gain-of-function variant inCACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role ofCACNA1C variants in neurodevelopmental disorders. Here, we useegl-19, theC.elegans homolog ofCACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that anegl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior inC.elegans. We find that wildtypeegl-19 negatively regulates axon termination. Theegl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that theegl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby ade novo mutation inCACNA1C can drive alterations in circuit formation and behavior.
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research