TMTC3 (transmembrane O-mannosyltransferase targeting cadherins 3) is an endoplasmic reticulum (ER)-localized enzyme that catalyzes the transfer of mannose residues to serine/threonine hydroxyl groups on target proteins 1. The protein functions as part of a four-member TMTC family dedicated to O-mannosylation of the cadherin superfamily, with TMTC3 specifically supporting O-linked glycosylation of E-cadherin and promoting cellular adhesion 2. Structurally, TMTC3 contains 11 transmembrane domains and belongs to the GT-C/PMT superfamily of sugar transferases, with conserved motifs for metal ion binding and dolichyl-phosphate-mannose recognition 1. Beyond glycosylation, TMTC3 serves as an ER stress mediator that disrupts PERK-GRP78 interactions to activate PERK signaling pathways 3. The protein localizes to GABAergic presynaptic terminals in the brain, suggesting involvement in inhibitory synapse regulation 4. Clinically, TMTC3 mutations cause lissencephaly-8, characterized by intellectual disability, epilepsy, periventricular nodular heterotopia, and neuronal migration defects 54. TMTC3 is also implicated in cancer progression, promoting epithelial-mesenchymal transition and tumor angiogenesis through various signaling pathways including Rho GTPase/STAT3/VEGFA 6. The protein's dual roles in neurodevelopment and cancer make it a potential therapeutic target.