An autism-associated calcium channel variant causes defects in neuronal polarity in the ALM neuron of C. elegans.

Abstract

Variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including bipolar disorder, schizophrenia, and ADHD. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. In our previous work, we demonstrated that an egl-19(gof) mutation, which is equivalent to the Timothy syndrome mutation in CACNA1C, can disrupt termination of the PLM axon in C. elegans. Here, we report a novel phenotype for the egl-19(gof) mutation, whereby it causes the growth of an ectopic process from the ALM cell body. We also extend our previous results to show that the egl-19(gof) mutation causes axon termination defects not only in the PLM axon, but also in the ALM axon. These results suggest that the Timothy syndrome mutation can disrupt multiple steps of axon development. Further work exploring the molecular mechanisms that underlie these perturbations in neuronal polarity and axon termination will give us better understanding of how variants in CACNA1C contribute to the axonal defects that underlie autism.