POMGNT2 (protein O-linked mannose N-acetylglucosaminyltransferase 2) is a glycosyltransferase enzyme that catalyzes the transfer of UDP-N-acetyl-D-glucosamine to the 4-position of O-mannose residues, generating the core M3-type O-mannosyl glycan structure essential for α-dystroglycan function 1. This enzyme localizes to the endoplasmic reticulum and displays significant amino-acid selectivity, recognizing specific TPT motif sequences through its N-terminal catalytic domain while its C-terminal fibronectin type III domain stabilizes peptide binding 12. The functional glycosylation catalyzed by POMGNT2 is critical for α-dystroglycan's high-affinity binding to laminin G-like domain-containing extracellular matrix proteins, thereby maintaining tissue integrity and neuromuscular stability 1. Loss-of-function mutations in POMGNT2 disrupt this post-translational modification pathway, causing α-dystroglycanopathy, a group of congenital muscular dystrophies presenting with variable phenotypes ranging from severe Walker-Warburg syndrome with brain and eye anomalies to limb-girdle forms 34. Crystal structure analysis has elucidated molecular bases for disease-associated mutations and provided mechanistic insights into POMGNT2's substrate recognition 3. Additionally, reduced POMGNT2 expression has been documented in various human cancers, suggesting potential involvement in cancer pathogenesis 56.