LYST is a large cytosolic protein that influences the biogenesis of 
lysosome-related organelles, and mutation of the encoding gene, LYST, can cause 
Chediak-Higashi syndrome. Recently, Lyst-mutant mice were recognized to also 
exhibit an iris disease resembling exfoliation syndrome, a common cause of 
glaucoma in humans. Here, Lyst-mutant iris phenotypes were used in a search for 
genes that influence Lyst pathways. In a candidate gene-driven approach, albino 
Lyst-mutant mice homozygous for a mutation in Tyr, whose product is key to 
melanin synthesis within melanosomes, exhibited complete rescue of Lyst-mutant 
iris phenotypes. In a genetic background-driven approach using a DBA/2J strain 
of congenic mice, an interval containing Tyrp1 enhanced Lyst-dependent iris 
phenotypes. Thus, both experimental approaches implicated the melanosome, an 
organelle that is a potential source of oxidative stress, as contributing to the 
disease phenotype. Confirming an association with oxidative damage, Lyst 
mutation resulted in genetic context-sensitive changes in iris lipid 
hydroperoxide levels, being lowest in albino and highest in DBA/2J mice. 
Surprisingly, the DBA/2J genetic background also exposed a late-onset 
neurodegenerative phenotype involving cerebellar Purkinje-cell degeneration. 
These results identify an association between oxidative damage to lipid 
membranes and the severity of Lyst-mutant phenotypes, revealing a new mechanism 
that contributes to pathophysiology involving LYST.