How a Defective Brain Transport Protein Can Lead to Severe Epilepsy
Researchers have uncovered how mutations in the SLC13A5 transporter impair citrate uptake in neurons, leading to severe epilepsy and developmental delays. This study advances understanding of genetic causes of neurological disorders and paves the way for targeted treatments.
Recent research has shed light on how mutations in a specific brain transport protein, SLC13A5, can cause a severe form of epilepsy known as developmental epileptic encephalopathy (DEE). Citrate, a crucial molecule in neuronal metabolism and function, relies on this transporter for proper cellular uptake. When SLC13A5 malfunctions due to genetic mutations, citrate transport is impaired, disrupting neuronal activity and development.
Building upon data from the RESOLUTE and REsolution projects, scientists at CeMM have conducted a comprehensive study of the structure and function of SLC13A5, analyzing nearly 10,000 genetic mutations through advanced deep mutational scanning techniques. From this vast dataset, 38 mutant variants were selected for detailed experimental analysis, revealing various molecular mechanisms by which these mutations influence transporter production, localization, and citrate transport efficiency.
The findings demonstrate that different mutations affect SLC13A5's stability and behavior within cells, contributing to the disease pathology. Identifying and characterizing these disease-causing variants significantly advances our understanding of how genetic mutations lead to neurological disorders such as epilepsy.
Citrate’s role in neuronal function is vital, as it influences neuronal signaling and brain metabolism. The disruption of citrate transport due to faulty SLC13A5 protein impairs neural development and function, resulting in severe epileptic symptoms and developmental delays. These insights open new avenues for targeted therapeutic strategies aimed at correcting or compensating for these genetic defects, potentially improving outcomes for affected individuals.
The research highlights the importance of systematic genetic variant investigation, especially in rare diseases. By understanding the molecular effects of specific mutations, scientists can better grasp disease mechanisms and develop precise interventions.
Source: https://medicalxpress.com/news/2025-06-faulty-protein-brain-trigger-severe.html
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