title: Melanocyte-specific proteins are aberrantly trafficked in melanocytes of Hermansky-Pudlak syndrome-type 3.
abstract: Hermansky-Pudlak Syndrome-type 3 (HPS-3) is a relatively mild subtype of HPS with minimal cutaneous and ocular depigmentation. The HPS-3 gene encodes a novel protein of unknown function with a predicted molecular weight of 114 kd. To assess the role of the HPS3 protein in melanization, cultured melanocytes developed from HPS-3 patients were evaluated biochemically and histologically for activity and localization of melanocyte-specific proteins. Endogenous tyrosinase activity of HPS-3 melanocytes was substantial, but tyrosinase activity and melanin synthesis was suppressed in intact melanocytes. However, the level of suppression, as well as extent to which up-regulation by isobutylmethylxanthine and cholera toxin was muted, was less that in HPS-1 melanocytes. Ultrastructurally, HPS-3 melanocytes contained morphologically normal melanosomes, predominantly of stage I and II with minimal stage III and few stage IV melanosomes. Dihydroxyphenylalanine (DOPA) histochemistry demonstrated an increase in melanization of melanosomes. Unique to HPS-3 melanocytes were numerous DOPA-positive 50-nm vesicles and tubular elements present throughout the cell body and dendrites. Tyrosinase, tyrosinase-related protein-1 (Tyrp1), dopachrome tautomerase (Dct), and LAMP1 and 3 localization in HPS-3 melanocytes, as evaluated by immunocytochemistry and confocal microscopy, demonstrated a fine, floccular distribution in contrast to the coarse, granular distribution characteristic of control melanocytes. The localization profile of other proteins expressed by melanocytes (ie, Silver/Pmel17, Melan-A/MART-1, LAMP2, Rab 27, transferrin, c-kit, adaptin-3, and the HPS1 protein) appeared normal. These results suggest that a specific subset of melanocyte proteins are aberrantly trafficked throughout the HPS-3 melanocyte and may be responsible for the reduction in melanin synthesis.
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML-0592, Cincinnati, OH 45267-0592, USA. boissyre@ucmail.uc.edu
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
authors.forename: Bonnie
authors.initials: B
authors.lastname: Richmond
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Amanda
authors.initials: A
authors.lastname: Helip-Wooley
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Amy
authors.initials: A
authors.lastname: Koshoffer
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D005123:Eye / Q000473:pathology; D022861:Hermanski-Pudlak Syndrome / Q000145:classification / Q000473:pathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D007980:Levodopa / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000473:pathology* / Q000502:physiology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D010858:Pigmentation; D021381:Protein Transport; D012867:Skin / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C432680:HPS3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D007980:Levodopa