# Investigating Divergent Disease Severity in Human Neuronal Models of KCNQ2-Related Developmental and Epilepsy Disorders

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $200,000

## Abstract

Mutations in KCNQ2 encoding voltage-gated K+ (KV7.2) channel are associated with monogenic early-onset
childhood epilepsies with overlapping characteristics but divergent clinical severity. The clinical spectrum of
KCNQ2-related epilepsy disorders ranges from autosomal-dominant Benign Familial Neonatal Seizures (BFNS)
to sporadic cases of severe Developmental and Epileptic Encephalopathy (DEE). Mutations in KCNQ2 account
for approximately 5% of all mutations identified in genetic epilepsy and 10% of those associated with early-onset
epilepsy. The mechanisms that drive the differential severity between BFNS and DEE cases are poorly
understood. Currently 30% of all epilepsy patients are completely refractory to any existing anti-epileptic
treatments and there are no treatments for the lifelong developmental and physical disabilities associated with
DEE. Thus, addressing this overarching question can facilitate development of novel and targeted therapeutic
strategies. Studies using heterologous expression systems and mouse models have provided many advances
in our understanding of KCNQ2-related epilepsies, but fail to account for some of the sources of phenotypic
variation associated with cellular and network-level development of the human brain. As a result of these
limitations there is a fundamental need to develop more human-relevant model systems for epilepsy. Recent
advances in the generation of human patient-specific induced pluripotent stem cells (hiPSCs) have allowed
patient somatic cells to be reprogrammed to pluripotency and differentiated into neurons. Thus, the present
proposal seeks to take advantage of these technologies to address how stable mutations in KCNQ2 affect: 1)
intrinsic and network excitability in specific human neuronal subtypes and 2) electrophysiological maturation and
plasticity of complex neuronal networks to determine whether these properties are altered in a disease-severity
specific manner. Here, we will use an established patient-specific iPSC-based platform to determine how BFNS
and DEE variants differentially impact human neurons using patch-clamp electrophysiology and multi-electrode
array (MEA) techniques.

## Key facts

- **NIH application ID:** 10526435
- **Project number:** 5R21NS125503-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Dina Simkin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2021-12-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526435

## Citation

> US National Institutes of Health, RePORTER application 10526435, Investigating Divergent Disease Severity in Human Neuronal Models of KCNQ2-Related Developmental and Epilepsy Disorders (5R21NS125503-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10526435. Licensed CC0.

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