POGLUT2 (protein O-glucosyltransferase 2) is a UDP-glucose-dependent glycosyltransferase that catalyzes O-glucose modification of serine residues within EGF repeats of extracellular proteins 1. The enzyme recognizes a consensus sequence (C3-x-x-x-x-x-S-x-x-C4) and exhibits substrate selectivity through recognition of conserved hydrophobic patches within properly folded EGF domains 2. POGLUT2 primarily targets Notch receptors (NOTCH1, NOTCH3) and extracellular matrix proteins including fibrillin-1, fibrillin-2, and LTBP1, modifying over half of their EGF repeats 3. The modification at the ligand-binding interface of NOTCH1 EGF11 fine-tunes Notch signaling pathway activation and affects cell-surface presentation of Notch receptors 1. POGLUT2 and its homolog POGLUT3 function redundantly in promoting fibrillin secretion and proper microfibril assembly in the extracellular matrix 3. Disease relevance is substantial: Poglut2/3 double knockout mice exhibit neonatal lethality with skeletal, pulmonary, and ocular defects resembling fibrillin/elastin mutations, including fragmented microfibrils and impaired elastic fiber formation 4. Marfan syndrome-associated FBN1 variants can produce aberrant O-glucosylation patterns, potentially contributing to disease pathogenesis 5. These findings establish POGLUT2 as critical for elastic tissue development and suggest dysregulation contributes to developmental and connective tissue disorders.