ANK2
Mutations and variations in the ANK2 gene have been associated with a range of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and epilepsy. ANK2 encodes ankyrin-B, a scaffolding protein that plays essential roles in organizing membrane proteins and linking them to the submembranous cytoskeleton, particularly in neurons. In the nervous system, ankyrin-B contributes to intracellular trafficking and axonal transport and is crucial for maintaining neuronal polarity and connectivity. Disruption of ankyrin-B function can lead to deficits in neuronal signaling and synaptic organization, potentially resulting in developmental and cognitive abnormalities. ANK2 gene is gaining recognition as a significant contributor to neurodevelopmental disease risk. Ongoing studies and advances in genetic diagnostics are expected to reveal more about the clinical spectrum associated with ANK2 mutations.
Biological Function
- Ankyrin-B anchors and stabilizes various ion channels (including sodium, potassium, and calcium channels) at the axon initial segment, nodes of Ranvier, and dendrites, ensuring proper neuronal excitability and signal transmission.
- The 440 kDa isoform of ankyrin-B is essential for axonal integrity, guiding microtubule bundling and suppressing excessive axonal branching, which is critical for maintaining proper neural circuit formation.
- Ankyrin-B regulates dendritic spine density and morphology, particularly in the prefrontal cortex, and is involved in synaptic signaling through interactions with L1CAM family adhesion molecules and voltage-gated sodium channels like NaV1.2.
- ANK2 expression is tightly regulated via transcriptional, translational, and post-translational mechanisms, including microRNA-mediated modulation and ubiquitin-proteasome degradation. Disruption of these processes can contribute to neurodevelopmental disorders.
- Mutations in ANK2 lead to hyperexcitability, disrupted network synchrony, and altered synaptic strength. These changes are implicated in the pathophysiology of autism spectrum disorder and epilepsy, suggesting a shared molecular basis for these conditions.
Mutations
Read this relevant article, "Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions and implications for autism spectrum disorder and epilepsy."
Research at Northwestern
The following studies highlight recent findings from Northwestern University researchers: