LARGE2 is a bifunctional glycosyltransferase that catalyzes both xylosyl- and glucuronyltransferase activities to generate xyloglucuronan polysaccharides composed of repeating [-3-Xylose-α1,3-GlcA-β1-] units 1. Its primary function is maturation of α-dystroglycan (α-DG) through O-linked glycosylation, enabling high-affinity binding to laminin and other extracellular matrix proteins 2. LARGE2 is more effective than its paralog LARGE1 at supporting α-DG maturation and can also modify proteoglycans like GPC4. Mechanistically, LARGE2 expression is regulated by canonical Wnt signaling via TCF7L2 binding to its promoter and is repressed by EMT transcription factors Snail and ZEB1 34. In disease contexts, LARGE2 downregulation associates with α-DG hypoglycosylation and loss of laminin-binding capacity in multiple cancers, including prostate and renal cell carcinomas, correlating with disease progression and metastasis 56. LARGE2 dysfunction also contributes to dystroglycanopathies when mutations impair glycosylation of α-DG, leading to muscular dystrophy and potentially neurological complications 7. Restoring LARGE2 expression or activity represents a potential therapeutic strategy for both cancer and muscular dystrophy.