Abnormal Expression and Subcellular Distribution of Subunit Proteins of the AP-3 Adaptor Complex Lead to Platelet Storage Pool Deficiency in the Pearl Mouse

• Published in: Blood Vol. 94; no. 1; pp. 146 - 155
• Main Authors: Zhen, Lijie, Jiang, Shelley, Feng, Lijun, Bright, Nicholas A., Peden, Andrew A., Seymour, Albert B., Novak, Edward K., Elliott, Rosemary, Gorin, Michael B., Robinson, Margaret S., Swank, Richard T.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.07.1999; The Americain Society of Hematology
• Subjects: Adaptor Protein Complex alpha Subunits; Adaptor Proteins, Vesicular Transport; Albinism, Oculocutaneous - blood; Albinism, Oculocutaneous - genetics; Albinism, Oculocutaneous - pathology; Animals; Biological and medical sciences; Biological Transport; Blood Platelets - physiology; Blood Platelets - ultrastructure; Gene Expression; Hematologic and hematopoietic diseases; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred C3H; Monomeric Clathrin Assembly Proteins; Mutation; Platelet diseases and coagulopathies; Platelet Storage Pool Deficiency - blood; Platelet Storage Pool Deficiency - genetics; Platelet Storage Pool Deficiency - pathology; Animal model; Storage pool disease; Pathogenesis; Rodentia; Hemopathy; Gene expression; Subunit; Vertebrata; Platelet; Mammalia; Mouse; Animal; Genetics; Carrier protein
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.1.146.413k39_146_155

The pearl mouse is a model for Hermansky Pudlak Syndrome (HPS), whose symptoms include hypopigmentation, lysosomal abnormalities, and prolonged bleeding due to platelet storage pool deficiency (SPD). The gene for pearl has recently been identified as the beta3A subunit of the AP-3 adaptor complex. The objective of these experiments was to determine if the expression and subcellular distribution of the AP-3 complex were altered in pearl platelets and other tissues. The beta3A subunit was undetectable in all pearl cells and 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 diffuse cytoplasmic pattern. Ultrastructural abnormalities in mutant lysosomes were likewise apparent in mutant kidney and a cultured mutant cell line. Genetically distinct mouse HPS models had normal expression of AP-3 subunits. These and related experiments strongly suggest that the AP-3 complex regulates the biogenesis/function of organelles of platelets and other cells and that abrogation of expression of the AP-3 complex leads to platelet SPD.