# The role of NPRL2 loss in focal cortical dysplasia

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $40,809

## Abstract

Project Summary
Malformations of brain development are a common cause of neurological disorders in children. The most
common of these neurodevelopmental disorders is the large group of malformations of cortical development
(MCD) characterized by disruption of the structure of the cerebral cortex (e.g., enhanced cell size, altered
lamination). Somatic mutations have been identified in regulatory genes of the PI3K-AKT3-mTOR (mTOR)
pathway in the brain tissue of patients with these MCD collectively termed ‘mTORopathies.’ Focal cortical
dysplasia is a particularly challenging mTORopathy due to the presence of highly epileptogenic lesions within
the cortex that are often resistant to medication and/or difficult to resect. The most common genetic variants
causing FCD are found in genes that encode protein subunits forming the GATOR1 complex: DEPDC5, NPRL2,
and NPRL3- a negative regulator of mTOR signaling. Many studies have linked variants in DEPDC5 and NPRL3
to mTOR pathway hyperactivation, MCD, and seizures, but there few studies functionally validating or modeling
variants in NPRL2 and, currently, mTOR inhibitors are not used to treat epilepsy in these patients. This project
seeks to investigate the effects of Nprl2 loss in vitro and in vivo and to identify the mTOR-dependent
transcriptomic changes that occur as a result of Nprl2 KO. The results of this proposal stand to provide a deep
functional and transcriptomic understanding of NPRL2 variant associated phenotypes, provide pre-clinical
support for the use of mTOR inhibitors in effected individuals, and identify novel therapeutic targets downstream
of mTOR that may provide precision therapy options in the future.

## Key facts

- **NIH application ID:** 11054709
- **Project number:** 3R01NS131223-02S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Philip Henry Iffland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,809
- **Award type:** 3
- **Project period:** 2023-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11054709

## Citation

> US National Institutes of Health, RePORTER application 11054709, The role of NPRL2 loss in focal cortical dysplasia (3R01NS131223-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11054709. Licensed CC0.

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