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Human Molecular Genetics, 2000, Vol. 9, No. 19 2781-2788
© 2000 Oxford University Press

Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1

Barbara Incerti1,+, Katia Cortese2, Alessandro Pizzigoni1, Enrico M. Surace1, Simona Varani1,§, Massimiliano Coppola1, Glen Jeffery3, Mathias Seeliger4, Gesine Jaissle4, Dorothy C. Bennett5, Valeria Marigo1,¶, Maria Vittoria Schiaffino1, Carlo Tacchetti2 and Andrea Ballabio1,6,¶

1Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, Via Olgettina 58, I-20132 Milan, Italy, 2Department of Experimental Medicine, Anatomy Section, University of Genova, I-16132 Genova, Italy, 3University College London, Institute of Ophthalmology, London, UK, 4Retinal Electrodiagnostics Research Group, University Eye Hospital, D-72076 Tübingen, Germany, 5St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK and 6Università Vita e Salute, San Raffaele, I-20132 Milan, Italy

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.

+ To whom correspondence should be addressed. Tel: +39 081 5790113; Fax: +39 081 5790919; Email: incerti@tigem.it

§ Present address: Department of Pathology, Baylor College of Medicine, Houston, TX 70030, USA

Present address: TIGEM, Via P. Castellino 11, I-80131 Naples, Italy


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