# Cellular and Temporal Dissection of KCNQ3 Gain-of-Function Disorder

> **NIH NIH R03** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $164,500

## Abstract

ABSTRACT
Intellectual disability and autism are caused – in up to 1 in 1,000 cases – by recurrent de novo missense variants
that alter a single arginine residue (R230) in the KCNQ3 gene. Patients with R230 variants have non-verbal
intellectual disability, autistic symptoms, and develop near-continuous multifocal spikes on
electroencephalography (EEG). KCNQ3 encodes a voltage-gated potassium channel that is active at
subthreshold potentials and concentrated at the axon initial segment, where it opposes depolarizing currents
that drive neurons to fire action potentials. We recently reported that R230 variants impart gain-of-function (GoF))
biophysical properties to the channel in vitro, but how these alterations lead to disease phenotypes is unknown.
Moreover, identification of the genetic etiology has yet to translate into targeted therapy. We have developed a
mouse model of the KCNQ3 GoF Disorder with a robust electroclinical phenotypes (frequent spike-wave
discharges and lowered electroconvulsive threshold) with relevance to the human condition. We now propose
the development of an innovative and versatile conditional version of this model to grant us control over
expression of the GoF mutant allele thereby permitting cellular and temporal dissection of the KCNQ3 GoF
Disorder. This mouse includes a floxed stop cassette for Cre recombinase mediated activation. In addition, the
GoF allele, (with an IRES-eGFP reporter) will be flanked by frt sites to permit Flpo recombinase mediated
deactivation. Using this tool to sequentially turn on and then off the GoF mutant channel with spatial and temporal
control, we will begin to dissect out (Aim 1. Cellular dissection) which neuronal populations are responsible for
the electroclinical phenotypes and (Aim 2. Temporal dissection) whether there are limited temporal windows for
preventing or reversing these phenotypes. We will begin these investigations with a pair of experiments that test
different aspects of the mouse design. In Aim 1, we will selectively activate the mutant allele in 1) inhibitory
neurons using a Gad2-IRES-Cre knock-in driver line, or in 2) excitatory neurons using an Emx-IRES-Cre knock-
in driver line, to ask if expression of the GoF allele in either broad neuronal subgroup is sufficient to reproduce
the robust electroclinical phenotypes observed in the constitutive GoF mutant mouse. In Aim 2, we will use an
inducible Flpo driver line, R26FlpoER, to examine the reversibility of the SWD phenotype. These experiments
represent only the introductory forays into the kind of genetic interrogations this conditional model will afford.
This genetic work is part of a larger program investigating the KCNQ3 GoF disorder, including extensive
electrophysiological investigations of the underlying physiology of impacted circuits and neurons. Pairing these
tools will advance our understanding and inform translational approaches to treatment.

## Key facts

- **NIH application ID:** 10591921
- **Project number:** 1R03NS127038-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** TRISTAN T SANDS
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $164,500
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591921

## Citation

> US National Institutes of Health, RePORTER application 10591921, Cellular and Temporal Dissection of KCNQ3 Gain-of-Function Disorder (1R03NS127038-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10591921. Licensed CC0.

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