# Understanding the Etiology of CASK Associated Epileptic Encephalopathy

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $415,368

## Abstract

PROJECT ABSTRACT
Epileptic encephalopathies (EEs) are severe brain disorders of early infantile and childhood age onset
characterized by epileptic seizures, abnormal electroencephalogram (EEG), severe cognitive and behavioral
impairments that might lead to early death. It is estimated that ~2.9 million Americans live with epilepsy and
the mortality rate in people with epilepsy is ~2-3 times higher than the general population. Several genetic
mutations associate with EEs including mutations in the X-linked intellectual disability gene CASK that are
found in patients with Ohtahara syndrome (OS) and West Syndrome (WS). Constitutive CASK deletion in
mammals is incompatible with life and the prognosis of CASK hemizygous male patients remains extremely
grim. The precise function of CASK and the potential mechanisms by which CASK mutation produces EE
remains obscure. Because the constitutive CASK-/- knockout mice exhibited neonatal lethality, we recently
generated a novel mouse model of EE by deleting CASK specifically from the neurons (CASKNKO). We found
that CASKNKO mice display severe growth retardation, recurrent tonic spasms, EEG anomalies, and
myoclonus beginning postnatal day 17 that leads to death by postnatal day 25. Multiple studies have shown
that CASK protein is localized at the mitochondrial membranes. Recently, CASK gene expression was found
to be regulated in an NAD+/Sirtuin1 dependent manner in mouse neurons. Moreover, we found that
mammalian CASK interacts and co-localizes with mitochondrial proteins, and significantly modulates
mitochondrial function and number. Based on the evidences from literature and our findings we hypothesize
that CASK plays a role in brain mitochondrial function and metabolism, and is critical for optimum neuronal
excitability in vivo. To test this hypothesis, we will examine the brain mitochondrial, metabolic, and
electrophysiological functional changes as well as synaptic excitatory/inhibitory balance in the CASKNKO mice.
We will further identify the specific domain/s of CASK that interacts with mitochondrial proteins, and determine
if SIRT1-dependent mitochondrial biogenesis pathway is dysregulated in the brain of CASKNKO mice.
Experiments will be performed before and after the onset of myoclonus to distinguish between a potential
cause and consequence relation with the disease. We will also test if pharmacological activation of
NAD+/SIRT1 pathway can stimulate mitochondrial biogenesis in the brain and CASK expression in glial cells
to rescue EE phenotype in the CASKNKO mice. Success in the proposed project will uncover how loss of
neuronal CASK alters mitochondrial and synaptic functions to produce EE. The long-term goal of our project
is to use the novel CASKNKO EE mouse model to identify potential disease biomarkers and test therapeutic
strategies for clinical intervention.

## Key facts

- **NIH application ID:** 10211576
- **Project number:** 1R01NS117698-01A1
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Sarika Srivastava
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,368
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10211576

## Citation

> US National Institutes of Health, RePORTER application 10211576, Understanding the Etiology of CASK Associated Epileptic Encephalopathy (1R01NS117698-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10211576. Licensed CC0.

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