# PCDH19-related Epilepsy-Human Genotype-Phenotype Studies Lead to Zebrafish Studies

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $387,188

## Abstract

Epilepsy is a common condition, affecting 1 in 26 individuals, for which the role of genetics is well recognized.
Since its discovery in 2008, PCDH19 has been amongst the most prominent single gene causes of epilepsy.
Mutations in PCDH19 cause X-linked “female limited epilepsy,” with refractory childhood-onset seizures,
intellectual disability, and autism. PCDH19 encodes a central nervous system protocadherin predicted to
mediate cell adhesion, but its role in neurodevelopment is not established. PCDH19 mutations can be de novo
or inherited from mildly affected/unaffected mothers or, curiously, unaffected fathers. The female
predominance is hypothesized to be due to ‘obligate mosaicism.’ Reports of rare symptomatic mosaic males
are consistent with this hypothesis. However, recently noted subtle behavioral features in ‘carrier’ fathers
suggest that a mosaic state is not required for all phenotypic manifestations. We will address, using these
unusual genetics as a clue, the functional role of PCDH19 and its role in epilepsy. We will conduct genotype-
phenotype studies to understand the importance of mutation location, type, and inheritance on PCDH19-
related dysfunction. We will then harness a carefully curated set of human PCDH19 mutations, from the
PCDH19 Registry that we founded, into zebrafish mechanistic models.
 There are currently no established animal models of PCDH19-induced epilepsy. Zebrafish represent an
established vertebrate model system with genetic tractability and identifiable seizures. Our preliminary data
from CRISPR/Cas9 genome-edited zebrafish suggest that loss of function of pcdh19 results in seizures. With
these models, we will study the cell types involved and the specific mechanisms by which loss or alteration of
pcdh19 results in disease. We hypothesize that the location and type of PCDH19 mutation correlates with
phenotypic severity in humans and that zebrafish models based on human mutations will display
seizures. We thus pursue a novel approach to study the mechanisms involved in PCDH19 dysfunction,
with models based on mutations that we have accrued through our Registry. We will aim to correlate the
severity of PCDH19-related phenotypes with location and type of patient mutations; establish pcdh19 zebrafish
models based on human mutations and characterize their epilepsy phenotypes; and identify the effects of
mutations on cell migration, adhesion, and excitability in mutant pcdh19 zebrafish.
Our research will develop the first in vivo animal models for PCDH19-related epilepsy. Through our zebrafish
models, we will investigate the neurodevelopmental role of PCDH19 and develop drug screens for PCDH19-
related epilepsy in the emerging era of precision medicine. The broader impacts of this study are that it will (1)
provide insight into protocadherin-related epilepsies, (2) establish a human-to-zebrafish paradigm for
translational research in genetic epilepsy, and (3) inform the modeling of other mosaic neurological disord...

## Key facts

- **NIH application ID:** 9832205
- **Project number:** 5R01NS100766-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Annapurna Poduri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,188
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832205

## Citation

> US National Institutes of Health, RePORTER application 9832205, PCDH19-related Epilepsy-Human Genotype-Phenotype Studies Lead to Zebrafish Studies (5R01NS100766-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9832205. Licensed CC0.

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