# Molecular mechanism of citrate transporter NaCT and its mutations that cause pediatric epilepsies

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $484,669

## Abstract

SUMMARY
Epileptic encephalopathies are a heterogeneous group of severe seizure disorders accounting for approximately
25% of childhood epilepsies. Mutations in the neuronal citrate transporter SLC13A5/NaCT gene abolish its
functional activity, causing early onset epileptic encephalopathy (EOEE). The patients display seizures in the
first hours of life, and experience developmental delays. The Na+-driven citrate transporter (NaCT) is located in
the plasma membrane of neurons. As an intermediate of the citric acid cycle, citrate is critical for energy
production in the cell, and it acts as a precursor for the synthesis of lipids and neurotransmitters. Disruption of
this citrate import process is therefore understandably harmful to neurons. According to their cellular expression
patterns, mutations causing EOEE have been classified as two types. Whereas Type I (protein located in the
ER) reduces protein stability, Type II (protein located in the plasma membrane) directly affects the substrate and
sodium binding sites or blocks the conformational changes necessary for transport. Based on a homology model
of NaCT built from our crystal structure of the bacterial succinate transporter VcINDY, we postulate how each
type of mutation alters the NaCT structure and hinders transport activity. We will characterize the mechanisms
and structural changes using a combination of biochemical, biophysical and structural approaches. The results
will aid in the design of small molecule potentiators and folding correctors with the potential to help the young
patients.

## Key facts

- **NIH application ID:** 10393545
- **Project number:** 5R01NS108151-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DANENG WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $484,669
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393545

## Citation

> US National Institutes of Health, RePORTER application 10393545, Molecular mechanism of citrate transporter NaCT and its mutations that cause pediatric epilepsies (5R01NS108151-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10393545. Licensed CC0.

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