AP1S1 encodes the sigma 1A subunit of adaptor protein complex 1 (AP-1), which plays a critical role in intracellular protein trafficking and vesicle formation 1. The AP-1 complex mediates clathrin-coated vesicle assembly and protein cargo sorting between the trans-Golgi network, endosomes, and plasma membrane, particularly directing trafficking of copper pumps ATP7A and ATP7B 1. Mutations in AP1S1 cause MEDNIK syndrome, a rare autosomal recessive disorder characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia 23. Both truncating mutations and missense variants result in complete MEDNIK syndrome, with missense variants causing loss-of-function through impaired AP-1 complex assembly and defective sorting motif binding 3. In intestinal epithelial cells, AP1S1 deficiency causes barrier dysfunction with altered tight junction protein localization, decreased transepithelial resistance, and increased permeability 4. Beyond MEDNIK syndrome, AP1S1 dysfunction contributes to Alzheimer's disease pathogenesis through increased neuronal vulnerability to oxidative stress and amyloid-β toxicity 5, and regulates EGFR trafficking in cancer cells, with downregulation leading to lysosomal EGFR degradation 6. These findings establish AP1S1 as essential for cellular trafficking machinery and highlight its role in multiple disease contexts.