{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:18:12Z","timestamp":1791353892261,"version":"4.3.1"},"reference-count":35,"publisher":"The Company of Biologists","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,8,1]]},"abstract":"<jats:p>Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and\/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw\/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1(tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes,tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.<\/jats:p>","DOI":"10.1242\/jcs.00598","type":"journal-article","created":{"date-parts":[[2003,6,26]],"date-time":"2003-06-26T18:02:32Z","timestamp":1056650552000},"page":"3203-3212","source":"Crossref","is-referenced-by-count":161,"title":["Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the <i>underwhite<\/i> (<i>uw<\/i>) mutation. A model for oculocutaneous albinism (OCA) type 4"],"prefix":"10.1242","volume":"116","author":[{"given":"Gertrude-E.","family":"Costin","sequence":"first","affiliation":[{"name":"Pigment Cell Biology Section, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio C.","family":"Valencia","sequence":"additional","affiliation":[{"name":"Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfred D.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Pigment Cell Biology Section, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Lynn","family":"Lamoreux","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, Texas A and M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent J.","family":"Hearing","sequence":"additional","affiliation":[{"name":"Pigment Cell Biology Section, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042517410738900_REF1","doi-asserted-by":"crossref","unstructured":"Basrur, V., Yang, F., Kushimoto, T., Yasumoto, K., Muller, J.,Vieira, W. D., Watabe, H., Hearing, V. J. and Appella, E.(2003). Proteomic analysis of early melanosomes: Identification of novel melanosomal proteins. J. Prot. Res.2, 69-79.","DOI":"10.1021\/pr025562r"},{"key":"2021042517410738900_REF2","doi-asserted-by":"crossref","unstructured":"Baxter, L. L. and Pavan, W. J. (2002). The oculocutaneous albinism type IV gene Matp is a new marker of pigment cell precursors during mouse embryonic development. Mech. Dev.116,209-212.","DOI":"10.1016\/S0925-4773(02)00130-2"},{"key":"2021042517410738900_REF3","unstructured":"Boissy, R. E., Zhao, H., Oetting, W. S., Austin, L. M.,Wildenberg, S. C., Boissy, Y. L., Zhao, Y., Sturm, R. A., Hearing, V. J.,King, R. A. et al. (1996). Mutation in and lack of expression of tyrosinase related protein 1 (TRP1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as OCA3. Am. J. Hum. Gen.58,1145-1156."},{"key":"2021042517410738900_REF4","doi-asserted-by":"crossref","unstructured":"Chen, K., Manga, P. and Orlow, S. J. (2002). The pink-eyed dilution protein controls the processing of tyrosinase. Mol. Biol. 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