Fig. 7: Working model.

TUSC3 deficiency impairs ER magnesium uptake by disrupting its positive modulation of ERMA, an ER Mg²⁺ transporter. This leads to reduced ER [Mg²⁺], activation of ER stress via the PERK–eIF2α axis, and suppression of global translation, including synaptic proteins (PSD-93, PSD-95, GluA1). In parallel, CREB activity is reduced through impaired PI3K/AKT signaling. Together, these changes result in synaptic dysfunction, increased neuronal vulnerability (via CHOP), and ultimately cognitive and adaptive behavioral deficits. Notably, magnesium supplementation restores ER [Mg²⁺] levels, alleviates ER stress, and rescues synaptic and cognitive phenotypes in TUSC3-deficient mice, suggesting a potential therapeutic strategy for TUSC3-associated ID.