Abnormal expression and subcellular distribution of subunit proteins of the AP-3 adaptor complex lead to platelet storage pool deficiency in the pearl mouse

The pearl mouse is a model for Hermansky Pudlak Syndrome (HPS), whose sympt oms include hypopigmentation, lysosomal abnormalities, and prolonged bleedi ng due to platelet storage pool deficiency (SPD). The gene for pearl has re cently been identified as the beta3A subunit of the AP-3 adaptor complex. T he objective of these experiments was to determine if the expression and su bcellular distribution of the AP-3 complex were altered in pearl platelets and other tissues. The beta3A subunit was undetectable in all pearl cells a nd tissues. Also, expression of other subunit proteins of the AP-3 complex was decreased. The subcellular distribution of the remaining AP-3 subunits in platelets, macrophages, and a melanocyte derived cell line of pearl mice was changed from the normal punctate, probably endosomal, pattern to a dif fuse cytoplasmic pattern. Ultrastructural abnormalities in mutant lysosomes were likewise apparent in mutant kidney and a cultured mutant cell line. G enetically distinct mouse HPS models had normal expression of AP-3 subunits . These and related experiments strongly suggest that the AP-3 complex regu lates the biogenesis/function of organelles of platelets and other cells an d that abrogation of expression of the AP-3 complex leads to platelet SPD. (C) 1999 by The American Society of Hematology.