1. Aberrant Protein Trafficking Underlies Vision Defects Associated with Syndromic Albinism.
Syndromic albinism is a group of genetically inheritable conditions that result in systemic pathology in addition to pigmentation defects. All affected individuals exhibit vision problems and most are legally blind. The common feature among these various conditions involves defective protein trafficking of secretory vesicles and lysosomal function. However, it is unclear how defects in protein trafficking lead to photoreceptor cell death and vision loss. We identified a zebrafish mutant for vps11, one of the HOPS/C-Vps class of protein-sorting genes. We showed that loss of Vps11 function in these mutants leads to syndromic albinism, including severe degeneration of the retina and retinal pigmented epithelium (Thomas et al 2011). Current research focuses on determining the underlying cause of this degeneration phenotype. Specifically, we want to determine the role of Vps11 in vesicle transport, lysosomal function, and autophagy. We hypothesize that Vps11 functions in a cell-type specific manner at multiple stages in the endo-lysosomal system to maintain cell viability. Analysis of C-Vps function in zebrafish gives us a vertebrate model for elucidating the exact steps within the endolysosomal pathway that underlie retinal pathology in syndromic albinism.
Loss of Vps11 function leads to syndromic albinism. Compared to wild-type siblings (A-D), vps11(plt) mutants show reduced pigmentation in body melanophores (E, arrow), reduce pigmentation in the retinal pigmented epithelium of the eye (F-G, RPE), severe retinal degeneration that includes retinal detachments (G, asterisk), and reduced numbers of mature melanosomes in the RPE (H).