The Hermansky-Pudlak syndrome 3 (cocoa) protein is a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2)

Hermansky- Pudlak syndrome ( HPS) is a genetically heterogeneous inherited disease affecting vesicle trafficking among lysosome- related organelles. The Hps3, Hps5, and Hps6 genes are mutated in the cocoa, rubyeye-2, and ruby- eye mouse pigment mutants, respectively, and their human orthologs are mutated in HPS3, HPS5, and HPS6 patients. These three genes encode novel proteins of unknown function. The phenotypes of Hps5/ Hps5, Hps6/ Hps6 and Hps3/ Hps3, Hps6/ Hps6 double mutant mice mimic, in coat and eye colors, in melanosome ultrastructure, and in levels of platelet dense granule serotonin, the corresponding phenotypes of single mutants. These facts suggest that the proteins encoded by these genes act within the same pathway or protein complex in vivo to regulate vesicle trafficking. Further, the Hps5 protein is destabilized within tissues of Hps3 and Hps6 mutants, as is the Hps6 protein within tissues of Hps3 and Hps5 mutants. Also, proteins encoded by these genes co- immunoprecipitate and occur in a complex of 350 kDa as determined by sucrose gradient and gel filtration analyses. Together, these results indicate that the Hps3, Hps5, and Hps6 proteins regulate vesicle trafficking to lysosome- related organelles at the physiological level as components of the BLOC- 2 ( biogenesis of lysosome- related organelles complex- 2) protein complex and suggest that the pathogenesis and future therapies of HPS3, HPS5, and HPS6 patients are likely to be similar. Interaction of the Hps5 and Hps6 proteins within BLOC- 2 is abolished by the three- amino acid deletion in the Hps6(ru) mutant allele, indicating that these three amino acids are important for normal BLOC- 2 complex formation.