Overview

• Researchers applied deep mutational scanning to assess nearly ten thousand SLC13A5 gene variants and their impact on transporter function.
• Analysis revealed that specific mutations reduce protein expression, mislocalize the transporter in neuron membranes, and lower citrate uptake rates.
• Disrupted citrate transport in neurons is linked to developmental epileptic encephalopathy, a severe form of epilepsy with early-life seizures and neurodevelopmental impairment.
• The comprehensive findings, supported by patient data from the TESS Research Foundation, were published in Science Advances following computational stability analyses and experimental tests of 38 variants.
• Insights into variant effects offer biomarkers for pathogenic mutations and a foundation for precision therapies targeting SLC13A5 dysfunction in epilepsy and other neurological disorders.