Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes
Open accessAbstract
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.
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Melanosomes, where melanin production occurs, are lysosome-related organelles and have been implicated in the progression of disease associated with Lyst mutation in mice.
“Melanosomes, where melanin production occurs, are lysosome-related organelles and have been implicated in the progression of disease associated with Lyst mutation in mice (Trantow et al., 2010).”
From Population genomics reveal recent speciation and rapid evolutionary adaptation in polar bears (2014) · cites this paper as Trantow et al., 2010
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- [42]Perou CM Leslie JD Green W Li L Ward DM 1997 The Beige/Chediak-Higashi Syndrome Gene Encodes a Widely Expressed Cytosolic Protein. J Biol Chem 272 29790 29794 9368050
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- Authors
- Trantow, C. M., Hedberg-Buenz, A., Iwashita, S., Moore, S. A., & Anderson, M. G.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Anderson, Michael G.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-07-01
- Volume
- 6
- Issue
- 7
- Pages
- e1001008
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2895641
- OpenAlex
- W2091091395
- Cited by
- 32
- References
- 46
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 1
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Eye Institute (R01EY017673, EY017673)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Keywords
- LYST, Chediak-Higashi syndrome, lysosome-related organelles, iris diseases, pseudoexfoliation syndrome, glaucoma, TYR, TRP-1, melanosomes, oxidative stress, lipid hydroperoxides, membrane lipid peroxidation, genetic modifiers, Purkinje cell degeneration, neurodegeneration, melanogenesis
- MeSH terms
- Animals, Cell Membrane, Disease Models, Animal, Female, Humans, Iris, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mutation, Phenotype, Proteins, Exfoliation Syndrome, Oxidative Stress, Vesicular Transport Proteins, Intracellular Signaling Peptides and Proteins, Mice
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