Abstract
Hermansky-Pudlak Syndrome (HPS) is a set of genetically heterogeneous diseases caused by mutations in one of nine known HPS genes. HPS patients display oculocutaneous hypopigmentation and bleeding diathesis and, depending on the disease subtype, pulmonary fibrosis, congenital nystagmus, reduced visual acuity, and platelet aggregation deficiency. Mouse models for all known HPS subtypes have contributed greatly to our understanding of the disease, but many of the molecular and cellular mechanisms underlying HPS remain unknown. Here, we characterize ocular defects in the zebrafish (Danio rerio) mutant snow white (snw), which possesses a recessive, missense mutation in hps5 (hps5I76N). Melanosome biogenesis is disrupted in snw/hps5 mutants, resulting in hypopigmentation, a significant decrease in the number, size, and maturity of melanosomes, and the presence of ectopic multi-melanosome clusters throughout the mutant retina and choroid. snw/hps5I76N is the first Hps5 mutation identified within the N-terminal WD40 repeat protein-protein binding domain. Through in vitro coexpression assays, we demonstrate that Hps5I76N retains the ability to bind its protein complex partners, Hps3 and Hps6. Furthermore, while Hps5 and Hps6 stabilize each other's expression, this stabilization is disrupted by Hps5I76N. The snw/hps5I76N mutant provides a valuable resource for structure-function analyses of Hps5 and enables further elucidation of the molecular and cellular mechanisms underlying HPS.