# Convergent mechanisms for neurodevelopmental disorder genes

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $86,029

## Abstract

Convergent Mechanisms for Neurodevelopmental Disorder Genes
 Voltage-gated sodium channels (NaVs) are essential regulators of neuronal excitability, making the
dysfunction of NaVs a serious public health concern. Genetic variants in SCN2A and SCN8A, which encode the
neuronal sodium channels NaV1.2 and NaV1.6, respectively, have been identified in several human patient
cohorts of neurodevelopmental disorders, including autism spectrum disorder (ASD) and epileptic
encephalopathy (EE). The proper localization of NaVs is dependent on their interactions with ankyrins, a family
of intracellular scaffolding proteins that link essential membrane-bound proteins to the underlying cytoskeleton.
Our lab and others have established ankyrin-G, encoded by ANK3, as the master organizer of the axon initial
segment (AIS), a key site of neuronal excitability. Ankyrin-G scaffolds proteins to the AIS, including NaV1.2 and
NaV1.6. Our lab recently identified a critical interaction between NaV1.2 and ankyrin-B, encoded by ANK2, in
mature neocortical pyramidal cell dendrites, where NaV1.2 regulates dendritic excitability. Previous studies have
identified the key residues required for the binding of ankyrins and NaVs. The key residues required for the
interaction between ankyrin-B and NaV1.2 are found within the ankyrin-repeats of ankyrin-B and the intracellular
loop between domains II and III (II-III loop) of NaV1.2. These residues are conserved among ankyrin-B and
ankyrin-G, and NaV1.2 and NaV1.6. Despite this conservation, ankyrins and NaVs have distinct neuronal
localization, suggesting that regions outside of the required residues play a role in the coordination of NaVs.
However, it remains unknown which amino acid sequences determine binding affinity between ankyrins and
NaVs to mediate differential ankyrin-dependent coordination of NaVs.
 Our preliminary data indicate that mutations near the ankyrin/NaV binding interface affect the binding
affinity between ankyrin-B and NaV1.2. The effects of these mutations on the binding affinity between NaV1.2
and ankyrin-G, however, have not been characterized. Furthermore, potential interactions between ankyrin-B
and NaV1.6 have not been studied. Altered binding affinities could explain differences in the localization and
function of these proteins. In addition, limitations in immunocytochemistry techniques have prevented a close
study of NaV1.6 localization outside the AIS. These results would provide critical information regarding the
ankyrin-dependent coordination of NaVs and ultimately help us determine how dysfunction of ankyrins and NaVs
contribute to the etiology underlying neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 10947766
- **Project number:** 3R01MH126960-04S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kevin J Bender
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,029
- **Award type:** 3
- **Project period:** 2021-05-14 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10947766

## Citation

> US National Institutes of Health, RePORTER application 10947766, Convergent mechanisms for neurodevelopmental disorder genes (3R01MH126960-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10947766. Licensed CC0.

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