PLS3 (plastin 3) is an X-chrX actin-bundling protein that plays a critical role in bone homeostasis 1. The gene encodes T-plastin, which mediates actin filament formation and bundle assembly in multiple cell types 2. PLS3 functions in osteocytes, osteoblasts, and osteoclasts through regulation of mechanotransduction, calcium homeostasis, vesicle trafficking, and cell differentiation 3. Loss-of-function variants in PLS3 cause X-linked osteoporosis, an early-onset monogenic bone disease characterized by abnormal bone microarchitecture, reduced bone mineral density, and increased fracture risk 4. PLS3-defective individuals show markedly reduced trabecular and cortical bone density, decreased trabecular number, increased trabecular separation, and impaired bone strength 5. Males are predominantly affected, though severe phenotypes have been documented in heterozygous females 4. Biochemically, PLS3 mutation carriers display elevated serum dickkopf-1 (DKK1) concentrations, suggesting altered Wnt pathway regulation 6. Recent evidence indicates PLS3 pathology extends beyond simple actin-bundling deficiency, involving broader bone metabolic pathways including Wnt signaling 2. Clinical significance: PLS3 mutations account for approximately 2.9% of monogenic early-onset osteoporosis cases 4. Genetic testing is recommended for early-onset osteoporosis diagnosis, though treatment strategies remain under development 7.