Journal article
Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes
PLoS genetics, Vol.6(7), pp.e1001008-12
07/01/2010
DOI: 10.1371/journal.pgen.1001008
PMCID: PMC2895641
PMID: 20617205
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.
Details
- Title: Subtitle
- Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes
- Creators
- Colleen M Trantow - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, United States of AmericaAdam Hedberg-BuenzSachiyo IwashitaSteven A MooreMichael G Anderson
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.6(7), pp.e1001008-12
- DOI
- 10.1371/journal.pgen.1001008
- PMID
- 20617205
- PMCID
- PMC2895641
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- EY017673 / NEI NIH HHS R01 EY017673 / NEI NIH HHS
- Language
- English
- Date published
- 07/01/2010
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025580702771
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