Investigation of how axon development is disrupted by the autism-causing Timothy syndrome mutation.

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Autism is a highly heritable neurodevelopmental disorder that has been linked to variants in many genes. However, the biological basis of autism remains poorly understood. To gain insight into the mechanisms that cause autism, we are focusing on the Timothy syndrome mutation, a variant in the CACNA1C voltage gated calcium channel (VGCC). The Timothy syndrome mutation causes autism with high penetrance, providing a powerful avenue for investigation of the molecular mechanisms that underlie autism. Our preliminary data indicate that the Timothy syndrome mutation disrupts axon targeting in C. elegans, providing a model for understanding the role of VGCC variants in autism. In aim 1, we will investigate how VGCCs regulate axon targeting and how the Timothy syndrome mutation alters this process to affect axonal connectivity and behavior. In aim 2, we will investigate how the Timothy syndrome mutation alters autophagy and how alterations in this process affect axon targeting. In aim 3, we will determine if other missense mutations in VGCCs can alter axon targeting. These studies will provide insight into the biological basis for autism and will identify interactions between autism-linked genes that could potentially be used to predict and diagnose autism. Moreover, the CACNA1C gene has also been associated with schizophrenia, bipolar disorder, major depression and attention deficit hyperactivity disorder, suggesting that our results are likely to be more broadly applicable to other neuropsychiatric disorders.