Scientists have uncovered new insights into the role of a faulty brain protein, SLC13A5, in triggering a severe form of epilepsy. This breakthrough study, conducted by researchers at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, builds on data from the RESOLUTE and REsolution flagship projects. The findings, published in Science Advances, provide a deeper understanding of the disease’s mechanisms and pave the way for future research into epilepsy and related disorders.
The membrane transport protein SLC13A5 is crucial for neuronal metabolism and development, facilitating the uptake of citrate—a key component in cellular metabolism. When mutations occur in the SLC13A5 gene, they can lead to a severe form of epilepsy known as SLC13A5 Citrate Transporter Disorder, or developmental epileptic encephalopathy (DEE). This condition is characterized by impaired brain development and severe neurological symptoms.
Unraveling the Mystery of SLC13A5 Mutations
The research team at CeMM employed a technique called “deep mutational scanning” (DMS) to analyze nearly ten thousand genetic mutations affecting the SLC13A5 transport protein. This comprehensive approach allowed scientists to identify 38 specific mutant variants for detailed experimental investigation. The study revealed several molecular mechanisms linked to the disease, including differences in transporter production levels, localization in the cell membrane, and citrate transport rates.
“With these results, we were able to identify and characterize disease-causing variants of the SLC13A5 transporter,” explained co-first author Wen-An Wang. “In addition, by computationally analyzing the mutant variants, we assessed protein stability across different conformations and established an evolutionary conservation score for all variants,” added co-first author Evandro Ferrada.
The Impact of Genetic Diversity on Health
Senior author Giulio Superti-Furga emphasized the importance of systematically investigating genetic variants, particularly in rare diseases like SLC13A5 citrate transporter deficiency. “Our work highlights the importance of uncovering molecular disease mechanisms,” he stated. “At the same time, we gain valuable insights into the impact of variants that also occur in the general population—an important step toward a more comprehensive understanding of genetic diversity and its impact on human health.”
The study was supported by the REsolution consortium, following the RESOLUTE project, which functionally mapped the entire SLC transporter family. This large-scale initiative, led by Giulio Superti-Furga, aimed to decode the “logistics of the cell” and has significantly contributed to the understanding of cellular transport mechanisms.
Implications for Future Research and Treatment
The findings from this study not only enhance the understanding of SLC13A5-related epilepsy but also open new avenues for research into potential treatments. By identifying and characterizing the specific mutations involved, scientists can now focus on developing targeted therapies that address the underlying molecular mechanisms.
Patient data for the study was provided by the TESS Research Foundation, which is dedicated to advancing research on SLC13A5 citrate transporter deficiency. This collaboration underscores the importance of integrating clinical data with scientific research to drive progress in understanding and treating rare diseases.
As research continues, the hope is that these insights will lead to more effective interventions for those affected by this severe form of epilepsy, ultimately improving the quality of life for patients and their families.
