An Autism-Causing Calcium Channel Variant Functions With Selective Autophagy to Alter Axon Targeting and Behavior

PLoS Genet. 2019 Dec 5;15(12):e1008488. doi: 10.1371/journal.pgen.1008488. eCollection 2019 Dec.

Abstract

Common and rare variants of the CACNA1C 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 how CACNA1C variants affect cellular processes to alter neurodevelopment. 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. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-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 the egl-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 a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Autistic Disorder / pathology
  • Autophagy
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics*
  • Calcium Channels / genetics*
  • Calcium Channels, L-Type / genetics*
  • Disease Models, Animal
  • Female
  • Humans
  • Long QT Syndrome / genetics
  • Male
  • Muscle Proteins / genetics*
  • Mutation*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology*
  • Syndactyly / genetics

Substances

  • CACNA1C protein, human
  • Caenorhabditis elegans Proteins
  • Calcium Channels
  • Calcium Channels, L-Type
  • Egl-19 protein, C elegans
  • Muscle Proteins

Supplementary concepts

  • Timothy syndrome