m⁶A-dependent FMRP control of DGKκ translation underlies core Fragile X phenotypes

Loss of FMRP causes excessive neuronal protein synthesis contributing to widespread functional disturbances, yet the mechanisms linking FMRP to specific mRNA targets remain unclear. We show that FMRP promotes translation of the brain mRNA DGKκ by binding m⁶A-modified repetitive RNA motifs, thereby relieving a translational block encoded within its sequence.

FMRP loss sharply reduces neuronal DGKκ, and DGKκ depletion alone reproduces hallmark FXS phenotypes, including hyperactivity, compulsive behavior, overgrowth, dendritic spine abnormalities, overactivated diacylglycerol signaling and increased protein synthesis. These findings identify DGKκ as a key effector of FMRP function and establish a regulatory axis where m⁶A RNA modification modulates neuronal translation. This work defines new principles of translational control in neurodevelopmental disorders and positions DGKκ as a central driver of FXS pathogenesis.