title: Melanosomal defects in melanocytes from mice lacking expression of the pink-eyed dilution gene: correction by culture in the presence of excess tyrosine.
abstract: Mutations in the murine pink-eyed dilution (p) gene, or its human homologue P, result in oculocutaneous albinism. Melanocytes cultured from mice lacking p gene expression exhibit defective melanogenesis, but following culture in the presence of high concentrations of L-tyrosine, increased melanin deposition is observed. Electron microscopy and image analysis demonstrated that untreated p mutant melanocytes exhibited small melanosomes, largely of stages I-II. Following tyrosine treatment, increased proportions of stage III-IV melanosomes, almost normal in size, were observed. Levels of tyrosinase protein and to a lesser extent of tyrosinase-related protein-1 (TRP-1) were subnormal but rose dramatically following stimulation by tyrosine. Levels of TRP-2 and Pmel17/silver gene product were not altered, nor were the levels of mRNA for tyrosinase, TRP-1, TRP-2, or the Pmel17/silver gene product. As expected, the 110-kDa product of the p gene was absent from both stimulated and unstimulated p mutant cells. In a melanoblast line derived from the same mice, excess tyrosine failed to stimulate visible melanogenesis or increase the low levels of tyrosinase. The melanosomes in these cells were smaller still than those in the mutant melanocytes even when cultured in the presence of excess tyrosine. Thus, absence of the p gene product affects melanosomal structure and protein composition at the posttranscriptional level. These defects are correctable at least in part by supplementation with L-tyrosine.
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York 10016, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rosemblat
authors.forename: E V
authors.initials: EV
authors.lastname: Sviderskaya
authors.forename: D J
authors.initials: DJ
authors.lastname: Easty
authors.forename: A
authors.initials: A
authors.lastname: Wilson
authors.forename: B S
authors.initials: BS
authors.lastname: Kwon
authors.forename: D C
authors.initials: DC
authors.lastname: Bennett
authors.forename: S J
authors.initials: SJ
authors.lastname: Orlow
mesh_terms: D016115:Albinism, Oculocutaneous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002352:Carrier Proteins; D004790:Enzyme Induction; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D014442:Monophenol Monooxygenase / Q000096:biosynthesis; D009024:Morphogenesis; D010088:Oxidoreductases; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014443:Tyrosine / Q000494:pharmacology*; D058951:gp100 Melanoma Antigen
chemical_list: D002352:Carrier Proteins; D008543:Melanins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D058951:gp100 Melanoma Antigen; C076239:P protein, mouse; D014443:Tyrosine; D010088:Oxidoreductases; C489799:TYRP1 protein, human; C079621:Tyrp1 protein, mouse; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase