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Endoplasmic reticulum retention is a common defect associated with tyrosinase-negative albinism.

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 degrees C, but not at the nonpermissive 37 degrees C 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.

Pubmed ID: 10823941


  • Halaban R
  • Svedine S
  • Cheng E
  • Smicun Y
  • Aron R
  • Hebert DN


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 23, 2000

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR39848
  • Agency: NIAMS NIH HHS, Id: AR41942
  • Agency: NCI NIH HHS, Id: CA79864

Mesh Terms

  • Albinism, Oculocutaneous
  • Amino Acid Substitution
  • Animals
  • Calcium-Binding Proteins
  • Calnexin
  • Calreticulin
  • Cells, Cultured
  • Endoplasmic Reticulum
  • Golgi Apparatus
  • Humans
  • Melanocytes
  • Melanosomes
  • Mice
  • Mice, Mutant Strains
  • Microscopy, Fluorescence
  • Monophenol Monooxygenase
  • Point Mutation
  • Protein Binding
  • Protein Folding
  • Recombinant Fusion Proteins
  • Ribonucleoproteins
  • Transfection