{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:26:43Z","timestamp":1791116803567,"version":"4.1.0"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"11","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,5,23]]},"abstract":"<jats:p>Tyrosinase is a melanocyte-specific enzyme critical for the synthesis of melanin, a process normally restricted to a post-Golgi compartment termed the melanosome. Loss-of-function mutations in tyrosinase are the cause of oculocutaneous albinism, demonstrating the importance of the enzyme in pigmentation. In the present study, we explored the possibility that trafficking of albino tyrosinase from the endoplasmic reticulum (ER) to the Golgi apparatus and beyond is disrupted. Toward this end, we analyzed the common albino mouse mutation Tyr(C85S), the frequent human albino substitution TYR(T373K), and the temperature-sensitive tyrosinase TYR(R402Q)\/Tyr(H402A) found in humans and mice, respectively. Intracellular localization was monitored in albino melanocytes carrying the native mutation, as well as in melanocytes ectopically expressing green fluorescent protein-tagged tyrosinase. Enzymatic characterization of complex glycans and immunofluorescence colocalization with organelle-specific resident proteins established that all four mutations produced defective proteins that were retained in the ER. TYR(R402Q)\/Tyr(H402A) Golgi processing and transport to melanosomes were promoted at the permissive temperature of 32\u00b0C, but not at the nonpermissive 37\u00b0C temperature. Furthermore, evidence of protein misfolding was demonstrated by the prolonged association of tyrosinase mutants with calnexin and calreticulin, known ER chaperones that play a key role in the quality-control processes of the secretory pathway. From these results we concluded that albinism, at least in part, is an ER retention disease.<\/jats:p>","DOI":"10.1073\/pnas.97.11.5889","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"5889-5894","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":159,"title":["Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism"],"prefix":"10.1073","volume":"97","author":[{"given":"Ruth","family":"Halaban","sequence":"first","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520; and Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA 01003"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherri","family":"Svedine","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520; 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