# Mouse models of Pik3ca brain overgrowth disorders

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $604,957

## Abstract

PROJECT SUMMARY
This proposal outlines a comprehensive series of experiments to assess the basis of overgrowth phenotypes
associated with gain of function mutations in PIK3CA, using the mouse as a model system. Although well
studied in cancer, recent data has revealed a role for PIK3CA mutation in several developmental disorders
including MCAP, DMEG, CLOVES syndrome, epidermal nevi and seborrheic keratosis. Here will assess the
developmental and signaling pathway disruptions caused by 3 different Pik3ca gain of function mutations, with
particular emphasis on the developing brain. To date, all reported PIK3CA mutations are postzygotic or mosaic
rather than germline mutations. Accordingly, we hypothesize that PIK3CA phenotypes correlate with both the
severity of the mutation and level (and distribution) of mosaicism. To test this and other hypotheses, we will
use standard conditional genetic approaches to express 3 patient-related Pik3ca gof mutations in embryonic
CNS neuronal progenitors and their descendants. We will then generate ES cell chimeras, injecting ES cells
constitutively expressing the same mutations into wild-type blastocysts to assess phenotype-mosaicism
relationships both within the brain and throughout the entire body. We also propose to use in utero
electroporation technology to more specifically target mosaic expression to the developing brain. Our studies
will assess the developmental pathogenesis of brain pathology and characterize the associated epilepsy, a
pressing clinically relevant phenotype. Finally, we will use pharmacological approaches to assess the
underlying mechanisms driving acutely Pik3ca-dependent seizures in post-natal mice. These assays represent
the first step toward developing molecularly rational epilepsy therapy in PIK3CA segmental brain overgrowth
syndrome patients.

## Key facts

- **NIH application ID:** 9905565
- **Project number:** 5R01NS099027-04
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Kathleen Joyce Millen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $604,957
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905565

## Citation

> US National Institutes of Health, RePORTER application 9905565, Mouse models of Pik3ca brain overgrowth disorders (5R01NS099027-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9905565. Licensed CC0.

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