title: Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5.
abstract: Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis resulting in melanosome dysfunction and absent platelet dense bodies. HPS patients have oculocutaneous albinism, bruising, and bleeding. HPS-5 results from deficiency of the HPS5 protein, a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). HPS5 has an unknown function and lacks homology to known proteins. We performed ultrastructural studies of HPS-5 melanocytes revealing predominantly early-stage melanosomes with many small 3,4(OH)2-phenylalanine-positive vesicles throughout the cell body and dendrites. These findings resemble the distinct ultrastructural features of HPS-3 melanocytes; HPS3 is also a BLOC-2 component. Immunofluorescence and immunoEM studies showed decreased TYRP1 labeling in the dendrites of HPS-5 melanocytes, and the overall abundance of TYRP1 was reduced. No substantial differences were observed in the distribution or abundance of Pmel17 in HPS-5 melanocytes. In normal melanocytes, endogenous tyrosinase colocalized with Pmel17 and TYRP1 in the perinuclear area and dendritic tips; this was much reduced in HPS-5 melanocytes, particularly in the tips. We conclude that early stage melanosome formation and Pmel17 trafficking are preserved in HPS5-deficient cells. Tyrosinase and TYRP1 are mistrafficked, however, and fail to be efficiently delivered to melanosomes of HPS-5 melanocytes.
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-1851, USA. ahwooley@mail.nih.gov
authors.forename: Amanda
authors.initials: A
authors.lastname: Helip-Wooley
authors.forename: Wendy
authors.initials: W
authors.lastname: Westbroek
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Dorward
authors.forename: Amy
authors.initials: A
authors.lastname: Koshoffer
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002451:Cell Compartmentation; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D008854:Microscopy, Electron; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C493900:HPS5 protein, human; D008562:Membrane Glycoproteins; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D014442:Monophenol Monooxygenase