# Convergent mechanisms for neurodevelopmental disorder genes

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $519,495

## Abstract

Thanks to the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk
genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). What
is currently missing is a mechanism linking these genes into a convergent pathway that gives insight into disease
etiology. In this proposal, we will test the hypothesis that ANK2 and SCN2A, two of the top genes implicated in
ASD, are linked at the molecular level to control dendritic excitability. NaV1.2, product of the SCN2A gene, is a
voltage-gated sodium channel found primarily in pyramidal neurons where it localizes to the axon initial segment
(AIS) early in development. Later in development, NaV1.2 relocalizes to dendrites where it plays critical roles in
synaptic plasticity and stability. The timing of the subcellular relocalization of NaV1.2 away from the AIS (~ 1 year
in humans) also correlates with the onset of symptoms in ASD patients, suggesting that understanding the new
role for NaV1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD. While our
group and others have shown that the intracellular scaffolding protein, ankyrin-G (ANK3), is necessary for NaV1.2
localization to the AIS, very little is known about the mechanisms underlying the dendritic localization of NaV1.2.
Ankyrin-B, product of the ANK2 gene, is a member of the ankyrin gene family that shares significant homology
with ankyrin-G, yet it is localized at high levels to dendrites where it may play a key role in NaV1.2 dendritic
localization. Testing the hypothesis that ANK2 and SCN2A are linked at the molecular level to control dendritic
excitability will have a positive impact by increasing our understanding of the mechanisms underlying synaptic
alterations in ASD, which may provide novel targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10772041
- **Project number:** 5R01MH126960-04
- **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:** $519,495
- **Award type:** 5
- **Project period:** 2021-05-14 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772041

## Citation

> US National Institutes of Health, RePORTER application 10772041, Convergent mechanisms for neurodevelopmental disorder genes (5R01MH126960-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10772041. Licensed CC0.

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