DEPDC5 Gene: Function, Mutations, and Role in Epilepsy | NCBI, UniProt, ClinVar

DEPDC5 (DEP domain containing 5) encodes a subunit of the GATOR1 complex, which negatively regulates the mTORC1 signaling pathway in response to amino acid deprivation. Loss-of-function mutations in DEPDC5 cause hyperactivation of mTORC1, leading to abnormal cell growth and neuronal migration defects. DEPDC5 is a major genetic cause of familial focal epilepsy with variable foci (FFEVF) and is associated with brain malformations such as focal cortical dysplasia type II (FCDII). The gene is widely expressed in brain tissues, particularly in the cerebral cortex and hippocampus.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• mTOR signaling pathway (KEGG hsa04150)

• GATOR1 complex regulation of mTORC1 (Reactome R-HSA-9639288)

• Amino acid sensing and mTORC1 activation (Reactome R-HSA-9639288)

DEPDC5 is a 1603-amino acid protein containing an N-terminal DEP domain (Dishevelled, Egl-10, Pleckstrin) and a C-terminal domain that mediates interaction with NPRL2 and NPRL3 to form the GATOR1 complex. GATOR1 acts as a GTPase-activating protein (GAP) for RagA/B, inhibiting mTORC1 under low amino acid conditions. DEPDC5 is essential for proper neuronal migration and cortical lamination; its loss leads to mTORC1 hyperactivation, aberrant cell growth, and epilepsy. The protein is predominantly cytoplasmic and enriched in brain tissue.