Work

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

Year: 2025

Type: article

Abstract: 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 (h DEPDC5 WT mice, h DEPDC5 F685L mice). Compared to wildtype (WT) and h DEPDC5 WT mice, h DEPDC5 F685L mice exhibited histological signs of mTOR hyperactivation, enlarged neuronal soma, abnormal neurons, and heightened susceptibility to seizures and mortality. Administering rapamycin to h DEPDC5 F685L 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 h DEPDC5 WT mice. Collectively, these results indicate that the DEPDC5 variant causes abnormal morphology and increased seizure vulnerability through modulation of mTOR signaling. • A DEPDC5 missense variant was identified in a three-generation Chinese epilepsy family • The DEPDC5 variant led to an increase in the surface area of the soma of neurons • The DEPDC5 variant increased seizure susceptibility and mortality • These findings support a precision medicine paradigm by using mTOR inhibitors in individuals carrying this variant to improve seizure control and reduce mortality

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.106842

Authors: Jie Liu, Rui Huang, Fenglin Tang, Yuanlin Ma, Patrick Kwan

Institutions: The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing Medical University, The Alfred Hospital, Monash University

Language: English

Topic: Epilepsy research and treatment

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,180