title: Melanocytes derived from patients with Hermansky-Pudlak Syndrome types 1, 2, and 3 have distinct defects in cargo trafficking.
abstract: Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disorder in which mutations in one of several genes interrupts biogenesis of melanosomes, platelet dense bodies, and lysosomes. Affected patients have oculocutaneous albinism, a bleeding diathesis, and sometimes develop granulomatous colitis or pulmonary fibrosis. In order to assess the role of HPS genes in melanosome biogenesis, melanocytes cultured from patients with HPS subtypes 1, 2, or 3 were assessed for the localization of various melanocyte proteins. Tyrosinase, Tyrp1, and Dct/Tyrp2 were atypically and distinctly expressed in HPS-1 and HPS-3 melanocytes, whereas only tyrosinase showed an atypical distribution in HPS-2 melanocytes. The HPS1 and AP3B1 (i.e., HPS-2) gene products showed no expression in HPS-1 and HPS-2 melanocytes, respectively, whereas HPS-3 melanocytes exhibited normal expression for both proteins. In normal human melanocytes, the HPS1 protein was expressed as an approximately 80 kDa molecule with both granular and reticular intracellular profiles. In HPS-1, lysosome associated membrane protein 1 (LAMP1), and LAMP3 were localized to abnormal large granules; in HPS-2, all LAMPs exhibited a normal granular expression; and in HPS-3, LAMP1, and LAMP3 exhibited a distinct less granular and more floccular pattern. In contrast, the expressions of Rab 27, transferrin, and cKit were unaffected in all three HPS genotypes. These data demonstrate that the three initially identified subtypes of human HPS exhibit distinct defects in the trafficking of various melanocyte-specific proteins.
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Richmond
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Jill
authors.initials: J
authors.lastname: Knapp
authors.forename: Amy
authors.initials: A
authors.lastname: Koshoffer
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
mesh_terms: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D059666:Lysosomal-Associated Membrane Protein 3
chemical_list: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; D015703:Antigens, CD; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D014442:Monophenol Monooxygenase; D009363:Neoplasm Proteins; D010088:Oxidoreductases; C439973:AP3B1 protein, human; C102160:HPS1 protein, human; C432680:HPS3 protein, human; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3; C489799:TYRP1 protein, human; C042501:dopachrome isomerase