Pharmacological Correction of Aberrant DSCAML1 Localization by 4-Phenylbutyrate Ameliorates Epileptic Phenotypes in a Mouse Model Harboring the Patient-Specific A2105T Mutation.

Abstract

DSCAML1 variants are associated with neurodevelopmental disorders and epilepsy. The pathogenic A2105T missense mutation leads to intracellular accumulation of the DSCAML1 protein, preventing its proper localization to the cell surface. Here, we investigated the therapeutic potential of 4-phenylbutyric acid (4PBA), a chemical chaperone, using a patient-derived Dscaml1knock-in mouse model. We demonstrated that 4PBA treatment restores the cell surface localization of the mutant DSCAML1 protein in primary cultured neurons. In the mouse model, oral administration of 4PBA ameliorated key neurodevelopmental deficits, including dendritic retraction in cortical layer V pyramidal neurons and abnormal clustering of somatostatin-positive interneurons in the hippocampus. Furthermore, 4PBA treatment significantly reduced the frequency of epileptic spike-and-wave discharges. These findings suggest that correcting the trafficking defect of DSCAML1 A2105T alleviates downstream neurological symptoms, highlighting the potential of chemical chaperones as a therapeutic strategy for DSCAML1-associated conformational disorders.