THAP12 (THAP domain containing 12) is an essential regulator of interferon-induced protein kinase R (PKR) signaling and early brain development. As an upstream regulator of PKR, THAP12 blocks the PKR-inhibitory function of DNAJC3, thereby restoring PKR kinase activity and suppressing cell growth [UniProt]. The protein mediates these effects through protein-protein interactions, notably with LDOC1 in regulating histone H2B monoubiquitination and chr11 accessibility in non-small cell lung cancer 1. Mechanistically, THAP12 dysfunction leads to loss-of-function phenotypes characterized by dysregulation of cell cycle and apoptotic pathways. Biallelic loss-of-function variants in THAP12 cause autosomal recessive developmental and epileptic encephalopathy (DEE), with patients presenting infantile spasms progressing to Lennox-Gastaut syndrome 2. Animal models confirm THAP12's dosage-sensitive essentiality: homozygous and compound heterozygous mice exhibit embryonic lethality, while zebrafish models recapitulate microcephaly, brain hypoplasia, abnormal neuronal activity, and increased seizure sensitivity 2. Wild-type human THAP12 rescues these phenotypes, whereas patient-derived variants do not 2. Clinically, THAP12 dysfunction represents a previously unrecognized cause of undiagnosed DEE cases, providing diagnostic and therapeutic targets for severe childhood neurological disorders.