Tyrosinase-negative and tyrosinase-positive oculocutaneous albinisms are autosomal recessive disorders in which there is no pigment, or minimally- detectable pigment, in the skin, hair, or eyes. The incidence of albinism in the United States is approximately 1:18,000, and the black population shows a high incidence. We hypothesize that the tyrosinase-negative form results from mutation of the tyrosinase gene, and that the tyrosinase- positive form results from mutation of the genes which control the eumelanin synthetic pathway, distal to tyrosinase catalysis. We have isolated a human tyrosinase gene and a candidate gene (pmel 17-1), whose product may be involved in controlling the eumelanin biosynthesis. In a study of a recessively-inherited albino family, structural differences in the tyrosinase locus were noted in two of those affected, as contrasted with their normal brother. The primary objective of this proposal is to classify the kinds of mutation in tyrosinase and pmel 17-1 genes in tyrosinase-negative and tyrosinase-positive albinos, and to develop a nucleic acid probe for prenatal diagnosis and improved carrier detection. To this end, we will determine the function of the pmel 17-1 gene product in eumelanin biosynthesis and will characterize the genomic organization of both the human tyrosinase and pmel 17-1 loci. We will analyze the restriction fragment length polymorphisms of tyrosinase and pmel 17-1 genes in tyrosinase-negative and -positive albino DNA, respectively, and will compare the mRNA expression and tyrosinase and pmel 17-1 cDNA sequences in albinos with the normal counterpart. Finally, we will express normal and mutated tyrosinase and pmel 17-1 genes in albino melanocytes, to confirm that the mutations result in the inactivity of the enzymes. Once we have identified and classified the pathologic lesions of mutant genes, we will design nucleic acid probes for prenatal diagnosis and improved carrier detection of tyrosinase-negative and tyrosinase-positive oculocutaneous albinism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR040248-05
Application #
2079936
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1990-06-01
Project End
1996-05-31
Budget Start
1994-06-01
Budget End
1996-05-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kwon, B S; Tan, K B; Ni, J et al. (1997) A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J Biol Chem 272:14272-6
Youn, B S; Kim, S H; Lyu, M S et al. (1997) Molecular cloning and characterization of a cDNA, CHEMR1, encoding a chemokine receptor with a homology to the human C-C chemokine receptor, CCR-4. Blood 89:4448-60
Lee, Z H; Hou, L; Moellmann, G et al. (1996) Characterization and subcellular localization of human Pmel 17/silver, a 110-kDa (pre)melanosomal membrane protein associated with 5,6,-dihydroxyindole-2-carboxylic acid (DHICA) converting activity. J Invest Dermatol 106:605-10
Youn, B S; Kim, K K; Kwon, B S (1996) A critical role of Sp1- and Ets-related transcription factors in maintaining CTL-specific expression of the mouse perforin gene. J Immunol 157:3499-509
Chakraborty, A K; Platt, J T; Kim, K K et al. (1996) Polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin by the pmel 17/silver locus protein. Eur J Biochem 236:180-8
Kim, K K; Youn, B S; Heng, H H et al. (1996) Genomic organization and FISH mapping of human Pmel 17, the putative silver locus. Pigment Cell Res 9:42-8
Hurtado, J C; Kim, S H; Pollok, K E et al. (1995) Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28. J Immunol 155:3360-7
Hou, L; Kwon, B S (1995) Turtle lung cells produce a melanization-stimulating activity that promotes melanocytic differentiation of avian neural crest cells. Pigment Cell Res 8:113-9
Zhou, Z; Kim, S; Hurtado, J et al. (1995) Characterization of human homologue of 4-1BB and its ligand. Immunol Lett 45:67-73
Youn, B S; Jang, I K; Broxmeyer, H E et al. (1995) A novel chemokine, macrophage inflammatory protein-related protein-2, inhibits colony formation of bone marrow myeloid progenitors. J Immunol 155:2661-7

Showing the most recent 10 out of 23 publications