PIGV encodes an alpha-1,6-mannosyltransferase that catalyzes a critical step in glycosylphosphatidylinositol (GPI) anchor biosynthesis 1. The enzyme transfers the second mannose via an alpha-1,6 bond from dolichol-phosphate-mannose to an intermediate substrate, participating in the seventh step of GPI-anchor biosynthesis. GPI-anchored proteins are essential for maintaining epithelial integrity during development, as demonstrated in C. elegans where PIGV reduction caused epithelial breaches, internal cysts, and surface ruptures during morphogenesis 1. These defects could be rescued by strengthening membrane-cortex connections, indicating GPI-anchored proteins are crucial for withstanding developmental stresses. PIGV mutations cause hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), characterized by intellectual disability, distinctive facial features, brachytelephalangy, and elevated serum alkaline phosphatase 23. The clinical spectrum also includes anorectal malformations, Hirschsprung disease, and renal anomalies 2. The most common mutation (c.1022C>A) accounts for approximately 80% of cases 24. Additionally, ER stress can downregulate PIGV through the ATF6-miR449c-5p pathway, contributing to cancer progression by disrupting GPI anchor assembly 5.