Convergence on CaMK4: A Key Modulator of Autism-Associated Signaling Pathways in Neurons

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent protein kinase 4) enzyme. CaMK4 is a key component of a Ca²⁺-activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss 3 genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on 4 other genetic variations in CAMK4 that show associations with autism spectrum disorder, as well as 12 examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight 3 environmental risk factors that impact CaMK4 signaling based on studies of preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest that defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and we propose CaMK4 as a potential therapeutic target.