MAGEL2 is a paternally expressed ubiquitin ligase regulator located within the Prader-Willi syndrome locus on chromosome 15-q13 1. It functions primarily as a co-factor enhancing E3 ubiquitin ligase activity and regulates endosomal protein recycling through the retromer pathway by promoting Lys-63-linked polyubiquitination of WASHC1, thereby facilitating endosomal F-actin assembly 2. MAGEL2 also represses circadian rhythm transcription by inhibiting CLOCK-BMAL1 activity and regulates RNA metabolism through interactions with proteins including SMN and FMRP 3. Loss-of-function MAGEL2 mutations cause Schaaf-Yang syndrome, a neurodevelopmental disorder characterized by autism spectrum disorder (up to 75% prevalence), joint contractures, and profound hypothalamic dysfunction 4. Pathogenic variants in MAGEL2 also contribute to arthrogryposis multiplex congenita, representing 21% of genetic causes in one cohort 5. Truncated MAGEL2 mutants show altered subcellular localization and reduced expression of PWS locus genes including SNORD116, bridging the phenotypic overlap between Schaaf-Yang and Prader-Willi syndromes 3. The gene's hypothalamic expression underlies its role in endocrine and metabolic regulation 6.