A missense variant in DEPDC5 resulted in abnormal morphology and increased seizure susceptibility and mortality through regulating mTOR signaling.

Dishevelled, Egl-10 and Pleckstrin domain-containing 5 (DEPDC5), a key inhibitor of the mammalian/mechanistic target of rapamycin (mTOR) pathway, is frequently associated with epilepsy. However, the functional consequences of most DEPDC5 variants rely on in silico predictions and have not been experimentally confirmed.This study aimed to determine the functional consequences of a DEPDC5 variant identified in patients with epilepsy across multiple generations in a Chinese family. We identified a missense heterozygous variant (c. 2055C > A; p. Phe685Leu) in DEPDC5 in Chinese family affected by epilepsy across three generations. This variant has not been previously reported in the Chinese population. Primary neuron cultures transfected with the mutant plasmid exhibited altered subcellular localization. To explore the mechanisms of epilepsy linked to this variant, we created nervous system-specific conditional human DEPDC5 knock-in mouse using Cre-recombination under the Nestin promotor (hDEPDC5 mice, hDEPDC5 mice). Compared to wildtype (WT) and hDEPDC5 mice, hDEPDC5 mice exhibited histological signs of mTOR hyperactivation, enlarged neuronal soma, abnormal neurons, and heightened susceptibility to seizures and mortality. Administering rapamycin to hDEPDC5 mice starting two weeks after birth normalized neuronal size and mTOR activity, decreased seizure susceptibility and mortality, and showed no effects in the WT or hDEPDC5 mice. Collectively, these results indicate that the DEPDC5 variant causes abnormal morphology and increased seizure vulnerability through modulation of mTOR signaling.