Melanosomes are cell-type-specific, membrane-bounded organelles in which melanin pigments are synthesized and stored. Abnormalities in melanosome biogenesis seem to underlie the pigmentation defects and visual problems associated with several human genetic disorders, such as X-linked ocular albinism 1 (OA1) and various types of Hermansky-Pudlak syndrome (HPS). Unlike OA1, all characterized types of HPS display additional clinical manifestations not related to melanosome function (e.g., prolonged bleeding), and are due to mutations in genes that are expressed ubiquitously. This has led to the idea that the products of HPS genes are involved in the biogenesis of several types of related organelles, including melanosomes, platelet dense granules and lysosomes. The goal of this project is to elucidate the function(s) of the products of the HPS1 and HPS4 genes, which are associated with two severe forms of HPS. Preliminary studies in our laboratory have revealed that HPS1 and HPS4 are components of a stable protein complex, termed Biogenesis of Lysosome-related Organelles Complex-3 (BLOC-3), which in fibroblasts is required for normal intracellular distribution of lysosomal-associated membrane proteins. The plan consists of three specific aims: (1) to determine the function of BLOC-3 in cells that contain lysosomes but lack specialized organelles such as melanosomes; (2) to determine the function of BLOC-3 in melanosome biogenesis, using primary melanocyte cultures from control and HPS1- or HPS4-mutant mice; and (3) to establish the mechanism(s) of action of BLOC-3 at the molecular level. This research may provide important insights into the basic question of how melanosomes and related organelles are formed, and pave the way for the development of potential treatments for HPS.
| Nazarian, Ramin; Huizing, Marjan; Helip-Wooley, Amanda et al. (2008) An immunoblotting assay to facilitate the molecular diagnosis of Hermansky-Pudlak syndrome. Mol Genet Metab 93:134-44 |
| Di Pietro, Santiago M; Falcon-Perez, Juan M; Tenza, Daniele et al. (2006) BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 17:4027-38 |
| Falcon-Perez, Juan M; Nazarian, Ramin; Sabatti, Chiara et al. (2005) Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in BLOC-3. J Cell Sci 118:5243-55 |
