Albinism is group of genetically inherited defects that occurs in 1 in 17,000 births and results in loss of pigmentation in the eyes, skin, and hair. All affected individuals exhibit vision problems and most are legally blind. However, the pathogenesis of photoreceptor loss in albino individuals is complex and is not well understood. In many cases, the data are contradictory in regard to how pigmentation affects photoreceptor viability. The zebrafish platinum mutant exhibits reduced pigmentation, degeneration of the retinal pigmented epithelium (RPE), and photoreceptor loss. We determined that platinum zebrafish contain a mutation in the vps11 (vacuolar protein sorting 11) gene, which is associated with Hermansky-Pudlak syndrome (HPS), a defined class of albinism that results from defective protein trafficking. Because there are currently no known mouse, fly, or worm mutants in the corresponding vps11 gene, we expect that our analysis of the platinum retinal pathology will contribute to broader understanding of the role of the vacuolar sorting proteins in HPS and the pathogenesis of photoreceptor loss in albino individuals. Genetic and cellular techniques will be used to determine the role of Vps11 in retinal and RPE development and examine how the platinum mutant develops its retinal phenotype. Specifically, knock-down and overexpression experiments will confirm that the platinum mutant phenotypes result from a mutation in the vps11 gene. Next, vps11 expression will be determined and the ocular platinum mutant phenotype will be assessed using behavioral, ultrastructural, immunohistochemical, and histological methods. Finally, the cell autonomy of the RPE and photoreceptor defects in the platinum mutant will be determined. This proposal will establish the platinum zebrafish mutant as a novel model for studying the mechanisms underlying vision defects associated with HPS and determine the role of the retinal pigmented epithelium in photoreceptor loss in albino individuals. The significance of the proposed research is to: 1) explore the consequences of Vps11 protein loss in the platinum mutant and 2) elucidate the cellular and molecular events leading to vision loss in one class of albinism. This work could ultimately reveal new targets for the development of therapies to prevent vision loss in persons afflicted with albinism.
All individuals affected with albinism exhibit vision problems and most are legally blind. However, the pathogenesis underlying photoreceptor loss in albinism is complex and poorly understood.
We aim to establish the platinum zebrafish mutant as a model for studying the mechanisms underlying vision defects associated with albinism.
