Human deficiencies of pigment formation, including oculocutaneous albinism are common genetic abnormalities with severe cutaneous and optic system effects. A reduction of melanin production in the skin results in a marked sensitivity to ultraviolet radiation and a predisposition of skin cancer. Reduction of melanin in the eye during development is associated with life- long nystagmus, foveal hypoplasia with reduced visual acuity, and abnormal routing of the neural connections from the retina to the brain, resulting in strabismus and loss of binocular vision. The clinical characteristics of six or more types of human oculocutaneous albinism have been described, and it is now clear that some of these result from different mutations at a single locus (allele heterogeneity), while others result from mutations at different loci (locus heterogeneity). The overall aims of this project are to investigate the clinical, ophthalmological, hematological, epidemiological, biochemical and molecular features of normal and abnormal human pigment formation, particularly oculocutaneous albinism. These studies will provide information which we hope will lead to methods of accurate diagnosis, therapy, and family counseling, so that these genetic diseases can be prevented, treated, or ameliorated. Four projects and a core facility will be utilized for this work. Project 1 will analyze the molecular and the biochemical characteristics of the different types of tyrosinase-related oculocutaneous albinism. Project 2 will analyze the defects in regulatory mechanisms and membranes in platelets and blood cells in patients with hypopigmentation, including the Hermansky-Pudlak syndrome. Project 3 will analyze the human correlate of the mouse pink-eyed dilution gene and will look for a type of human oculocutaneous hypopigmentation that is associated with changes in this gene. Project 4 will analyze the biology of the melanocyte int he different types of human oculocutaneous albinism. The core facility will provide support for the ophthalmologic evaluation of the patients seen in the different projects, for the biophysical analysis of the structure and function of the melanin isolated in the different projects, and for the development of a transgenic mouse model of pigmentation that can be used in the analysis of the effects of melanin on the development of the optic and auditory system.
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