Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome dueto mutations in the beta 3A subunit of the AP-3 adaptor

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defe ctive lysosome-related organelles. Here, we report the identification of tw o HPS patients with mutations in the P3A subunit of the heterotetrameric AP -3 complex. The patients' fibroblasts exhibit drastically reduced levels of AP-3 due to enhanced degradation of mutant beta 3A. The AP-3 deficiency re sults in increased surface expression of the lysosomal membrane proteins CD 63, lamp-1, and lamp-2, but not of nonlysosomal proteins. These differentia l effects are consistent with the preferential interaction of the AP-3 mu 3 A subunit with tyrosine-based signals involved in lysosomal targeting. Our results suggest that AP-3 functions in protein sorting to lysosomes and pro vide an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machin ery.