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The Ocular Albinism Type 1 (OA1) Gene Controls Melanosome Maturation and Size

³From the Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; ¹MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genoa, Genoa, Italy; and ⁴Medical Genetics, Department of Pediatrics, Federico II University, Naples, Italy.

PURPOSE. The authors took advantage of the Oa1 mutant mouse in combination with other albinism mouse models (i.e., Tyrosinase and membrane-associated transporter protein [Matp]) to study the function of Oa1, the gene mutated in ocular albinism type 1, in the RPE during development and after birth.

METHODS. Enzyme activity and protein localization were analyzed by immunohistochemistry of tyrosinase (Tyr) in Oa1-null mice. Ultrastructural analysis and morphometry were performed by electron microscopy, of the RPE in Oa1-knockout mouse and double-mutant mice of Oa1 with either Tyr or Matp.

RESULTS. Differently from other albinism models, Tyr activity was not impaired in Oa1^–/– eyes. Hypopigmentation of the RPE in Oa1^–/– mice is due to a reduced number of melanosomes. Analysis of Oa1^–/–;Tyr^c-2J/Tyr^c-2J and Oa1^–/–;Matp^uw/Matp^uw double-knockout mice, which display a block at stages II and III of melanosome maturation, respectively, revealed that Oa1 controls the rate of melanosome biogenesis at early stages of the organellogenesis, whereas the control on the organelle size is exerted at the final stage of melanosome development (stage IV).

CONCLUSIONS. The findings indicate that Oa1 is involved in the regulation of melanosome maturation at two steps. Acting at early maturation stages, Oa1 controls the abundance of melanosomes in RPE cells. At later stages, Oa1 has a function in the maintenance of a correct melanosomal size. This study helps to define ocular albinism type 1 as a defect in melanosome organellogenesis and not in melanin production.

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