ANK3
Mutations in the ANK3 gene have been associated with neuropsychiatric and neurodevelopmental disorders, most notably bipolar disorder, schizophrenia, autism spectrum disorder, and intellectual disability. ANK3 encodes ankyrin-G, a critical protein involved in the proper functioning of the neuronal axon initial segment (AIS), nodes of Ranvier, and post synaptic density, which are essential for the core framework for efficient communication in the nervous system. Disruption of ankyrin-G function can impair neuronal connectivity and signaling, potentially leading to cognitive and behavioral abnormalities. Although specific ANK3-related syndromes have not been universally defined, the gene is increasingly recognized as a key player in psychiatric genetics. Ongoing research and expanded genomic screening are likely to uncover additional cases and further clarify the clinical impact of ANK3 mutations.
- Ankyrin-G organizes the AIS by clustering voltage-gated sodium channels, cell adhesion molecules (like neurofascin), and cytoskeletal proteins. This scaffolding is essential for action potential initiation and maintaining neuronal polarity.
- At the Nodes of Ranvier, ankyrin-G ensures the correct localization and clustering of ion channels necessary for saltatory conduction in myelinated axons, contributing to rapid signal transmission.
- The 190 kDa isoform localizes to dendritic spines and plays a vital role in maintaining spine morphology and anchoring AMPA receptors, thereby facilitating synaptic transmission and plasticity.
- The 480 kDa isoform of ankyrin-G stabilizes GABAergic synapses at somatodendritic sites by interacting with GABARAP and opposing GABAA receptor endocytosis, which is critical for maintaining inhibitory tone.
- Ankyrin-G forms nanoscale domains at the spine neck, likely contributing to the compartmentalization of biochemical signals by restricting protein diffusion, akin to its role at the AIS.
- Through its membrane-binding and spectrin-binding domains, ankyrin-G links membrane proteins (e.g., ion channels and transporters) to the underlying cytoskeleton, modulating their localization and trafficking.
- Ankyrin-G integrates into protein networks linked to neuropsychiatric disorders such as bipolar disorder, schizophrenia, and autism. This involves diverse functions including isoform-specific expression, post-translational modifications (e.g., palmitoylation), and interaction with proteins such as SHANK, Homer1, and DAGLα.
The following studies highlight recent findings from Northwestern University researchers: