Oculocutaneous albinism (OCA) has been described as an inborn error of metabolism since 1908, yet little is known about the specific mechanisms of the mutations causing the 6 or more types found in humans. This is a common genetic abnormality found throughout the world with a frequency of 1:17,000 in the United States and at least 1:2,000 in Equatorial Africa. A reduction in melanin production in the skin can have devastating effects on the affected individual resulting in a marked sensitivity to ultraviolet radiation and a predisposition to skin cancer. Reduction of melanin in the eye during development is associated with life-long nystagmus, foveal hypoplasia with reduced visual acuity, and abnormal binocular vision. Diagnosis of OCA is based on imprecise clinical features and hairbulb tyrosinase activity. At present, no specific care related to the primary defect for each type is available, largely because the primary defect is unknown. Dopachrome oxidoreductase (DCOR) is a newly described enzyme in the melanin pathway. DCOR has been shown to be lacking in certain pigment mutants of the mouse and is expected to linked to a Form of albinism in humans. The goal of this proposal will be to isolate and characterize the gene for DCOR and to determine the role of this enzyme in normal and abnormal human melanin synthesis. This will require determining a partial amino acid sequence of the enzyme, and isolation of a DCOR cDNA clone utilizing oligonucleotide probes. The DCOR cDNA will then be used as a probe for the isolation of the genomic sequences for DCOR. Once isolated, the gene will be studied to determine the role it plays in human albinism. RFLP linkage analysis will be done on families with albinism using this gene to link DCOR to a specific type of albinism. Furthermore, genomic sequence information, including flanking regions, will allow comparisons to be made between the DCOR gene and other pigment genes in an attempt to find common sequences that control the formation of this major photoprotective pigment.
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