title: Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes.
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.
authors.affiliation: Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Trantow
authors.forename: Adam
authors.initials: A
authors.lastname: Hedberg-Buenz
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Iwashita
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Michael G
authors.initials: MG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004195:Disease Models, Animal; D017889:Exfoliation Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007498:Iris / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D018384:Oxidative Stress; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C491133:Lyst protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins