Albinism connotes a group of genetic disorders that share in common the reduction of ocular and often cutaneous pigmentation, and are associated with significant visual morbidity. Ocular Albinism Type 1 (Nettleship-Falls type) is the most common form of ocular albinism. To understand the pathogenesis of ocular albinism caused by mutations in the OA1 gene, the murine Oal gene product will be studied by a combination of cellular, molecular biologic, genetic and biochemical techniques. During the next five years of support, the four specific aims to be pursued will be to: 1. Define the subcellular distribution of Oa1 in pigment cells and when expressed in nonmelanocytic mammalian cells as well as in Saccharomyces cerevisiae. 2. Elucidate the sequences that direct Oal to its subcellular destination and the pathway by which it traffics to that destination. 3. Test hypotheses regarding the potential subcellular function of Oa1 in mammalian and in yeast-based model systems. 4. Identify proteins that interact with Oa1. Emphasis will be placed on understanding how specific mutations causing the clinical disorder OA1 affect the protein's localization, trafficking and function when introduced into Oal. This work will shed light both upon the means by which such mutations cause human visual disease as well as upon basic mechanisms in cell biology.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010223-12
Application #
6898151
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
1994-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
12
Fiscal Year
2005
Total Cost
$330,000
Indirect Cost
Name
New York University
Department
Dermatology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Bowling, Benjamin D; Doudican, Nicole; Manga, Prashiela et al. (2008) Inhibition of mitochondrial protein translation sensitizes melanoma cells to arsenic trioxide cytotoxicity via a reactive oxygen species dependent mechanism. Cancer Chemother Pharmacol 63:37-43
Sone, Michio; Orlow, Seth J (2007) The ocular albinism type 1 gene product, OA1, spans intracellular membranes 7 times. Exp Eye Res 85:806-16
Ni-Komatsu, Li; Orlow, Seth J (2007) Identification of novel pigmentation modulators by chemical genetic screening. J Invest Dermatol 127:1585-92
Ni-Komatsu, Li; Orlow, Seth J (2006) Heterologous expression of tyrosinase recapitulates the misprocessing and mistrafficking in oculocutaneous albinism type 2: effects of altering intracellular pH and pink-eyed dilution gene expression. Exp Eye Res 82:519-28
Staleva, Liliana; Orlow, Seth J (2006) Ocular albinism 1 protein: trafficking and function when expressed in Saccharomyces cerevisiae. Exp Eye Res 82:311-8
Hall, Andrea M; Orlow, Seth J (2005) Degradation of tyrosinase induced by phenylthiourea occurs following Golgi maturation. Pigment Cell Res 18:122-9
Staleva, Liliana; Hall, Andrea; Orlow, Seth J (2004) Oxidative stress activates FUS1 and RLM1 transcription in the yeast Saccharomyces cerevisiae in an oxidant-dependent Manner. Mol Biol Cell 15:5574-82
Hall, Andrea M; Krishnamoorthy, Lalitha; Orlow, Seth J (2004) 25-hydroxycholesterol acts in the Golgi compartment to induce degradation of tyrosinase. Pigment Cell Res 17:396-406
Beermann, Friedrich; Orlow, Seth J; Lamoreux, M Lynn (2004) The Tyr (albino) locus of the laboratory mouse. Mamm Genome 15:749-58
Chen, Kun; Manga, Prashiela; Orlow, Seth J (2002) Pink-eyed dilution protein controls the processing of tyrosinase. Mol Biol Cell 13:1953-64

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