GXYLT1 (glucoside xylosyltransferase 1) is a glycosyltransferase that elongates O-linked glucose attached to EGF-like repeats in Notch proteins by catalyzing xylose addition 1. This modification fine-tunes Notch signaling, with xylosylation serving as a negative regulator of Notch activation in mammalian cells 1. GXYLT1 expression is upregulated following ligand-induced Notch activation in acute myeloid leukemia cells, suggesting a feedback mechanism modulating Notch receptor sensitivity 2. GXYLT1 has emerged as a multifunctional protein with disease relevance beyond Notch glycosylation. A stop-gain mutation (GXYLT1S212*) in colorectal cancer promotes metastasis primarily through MAPK pathway activation, with GXYLT1 mutated in 40% of analyzed CRC samples 3. Genetic variants near GXYLT1 associate with glycemic response to sulfonylureas in type 2 diabetes, with the C allele at rs1234032 linked to reduced HbA1c reduction and increased glucose levels 4. Additionally, GXYLT1 variants show associations with granuloma formation in Crohn disease 5 and potential links to hypertension risk 6. GXYLT1 mutations have also been identified in carotid paragangliomas and psoriatic skin, indicating broader involvement in epithelial pathology 78.