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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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University of Minnesota Twin Cities
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Oetting, W S; Fryer, J P; Oofuji, Y et al. (1994) Analysis of tyrosinase gene mutations using direct automated infrared fluorescence DNA sequencing of amplified exons. Electrophoresis 15:159-64
Oetting, W S; King, R A (1994) Molecular basis of oculocutaneous albinism. J Invest Dermatol 103:131S-136S
Oetting, W S; King, R A (1994) Analysis of tyrosinase mutations associated with tyrosinase-related oculocutaneous albinism (OCA1). Pigment Cell Res 7:285-90
Oetting, W S; Witkop Jr, C J; Brown, S A et al. (1993) A frequent tyrosinase gene mutation associated with type I-A (tyrosinase-negative) oculocutaneous albinism in Puerto Rico. Am J Hum Genet 52:17-23
Oetting, W S; King, R A (1993) Molecular basis of type I (tyrosinase-related) oculocutaneous albinism: mutations and polymorphisms of the human tyrosinase gene. Hum Mutat 2:1-6
Oetting, W S; Stine, O C; Townsend, D et al. (1993) Evolution of the tyrosinase related gene (TYRL) in primates. Pigment Cell Res 6:171-7
Oetting, W S; Fryer, J P; King, R A (1993) A dinucleotide deletion (-delta GA115) in the tyrosinase gene responsible for type I-A (tyrosinase negative) oculocutaneous albinism in a Pakistani individual. Hum Mol Genet 2:1047-8
Oetting, W S; King, R A (1992) Molecular analysis of type I-A (tyrosinase negative) oculocutaneous albinism. Hum Genet 90:258-62
Oetting, W S; King, R A (1992) Analysis of mutations in the copper B binding region associated with type I (tyrosinase-related) oculocutaneous albinism. Pigment Cell Res 5:274-8
Oetting, W S; Mentink, M M; Summers, C G et al. (1991) Three different frameshift mutations of the tyrosinase gene in type IA oculocutaneous albinism. Am J Hum Genet 49:199-206

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