Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes

Colleen M. Trantow, Adam Hedberg-Buenz, Sachiyo Iwashita, Steven A. Moore, Michael G. Anderson

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalPLoS Genetics
Volume6
Issue number7
DOIs
StatePublished - Jul 2010

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    Trantow, C. M., Hedberg-Buenz, A., Iwashita, S., Moore, S. A., & Anderson, M. G. (2010). Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes. PLoS Genetics, 6(7), 1-12. https://doi.org/10.1371/journal.pgen.1001008