TMTC1 (transmembrane O-mannosyltransferase targeting cadherins 1) is an ER-resident O-mannosyltransferase that catalyzes the transfer of mannosyl residues to serine or threonine residues on target proteins 1. As a member of the TMTC1-4 family, TMTC1 belongs to the GT-C/PMT superfamily of sugar-transferring enzymes 2 and represents a distinct O-mannosylation pathway dedicated primarily to the cadherin superfamily and other adhesion molecules 1. TMTC1 modifies cadherins and integrins β1 and β4 through O-linked mannose glycosylation at specific Ig-like protein domains, facilitating cell-cell and cell-extracellular matrix interactions 3. Functionally, TMTC1 maintains vascular homeostasis as a Notch transcriptional target, interacting with VE-cadherin to regulate its ER egress and endothelial barrier integrity 4. Disease relevance includes ovarian cancer, where TMTC1 overexpression promotes cell invasiveness and poor prognosis through enhanced integrin-mediated migration and invasion 5. TMTC1 has also been implicated in schizophrenia pathogenesis through altered brain glycosylation patterns 6 and in hypertrophic cardiomyopathy, where downregulation in endothelial cells contributes to endothelial dysfunction 7.