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Oculocutaneous albinism types 1 and 3 are ER retention diseases: mutation of tyrosinase or Tyrp1 can affect the processing of both mutant and wild‐type proteins
Author(s) -
Toyofuku Kazutomo,
Wada Ikuo,
Valencia Julio C.,
Kushimoto Tsuneto,
Ferrans Victor J.,
Hearing Vincent J.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0216com
Subject(s) - tyrosinase , melanosome , mutant , melanin , melanocyte , oculocutaneous albinism , mutation , wild type , calnexin , biology , albinism , microbiology and biotechnology , er retention , genetics , gene , biochemistry , melanoma , enzyme , endoplasmic reticulum , calreticulin
Various types of oculocutaneous albinism (OCA) are associated with reduced pigmentation in the skin, hair, and eyes that results from mutations in genes involved in melanin synthesis. Immortal mouse melanocyte lines (melan‐a, melan‐b, and melan‐c) provide opportune models with which to investigate the etiology of two different types of OCA(types I and III), which arise from mutations in Tyr and Tyrpl , respectively. We compared intracellular processing, sorting, and degradation of tyrosinase and Tyrp1, and the effects on their catalytic function and melanin synthesis, in these wild‐type and mutant melanocytes. A mutation in either Tyr or Tyrp1 increased the time of association of tyrosinase and Tyrpl with calnexin and Bip, which in turn resulted in the retention of these mutant products in the ER. A mutation in either gene selectively enhanced the duration and efficiency of chaperone interactions (even with the wild‐type protein in the mutant melanocytes) and markedly slowed their transport to melanosomes. These results show that OCA1 and OCA3 are (in some cases, at least) ER retention diseases wherein a mutation in one melano‐genic protein affects the maturation and stability of the other in the melanogenic pathway.—Toyofuku, K., Wada, I., Valencia, J. C., Kushimoto, T., Ferrans, V. J., Hearing, V. J. Oculocutaneous albinism types 1 and 3 are ER retention diseases: mutation of tyrosinase or Tyrp1 can affect the processing of both mutant and wild‐type proteins. FASEB J. 15, 2149–2161 (2001)