title: Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration.
abstract: Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.
authors.affiliation: Department of Ophthalmology and Visual Science, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: G
authors.initials: G
authors.lastname: Karan
authors.forename: C
authors.initials: C
authors.lastname: Lillo
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: D J
authors.initials: DJ
authors.lastname: Cameron
authors.forename: K G
authors.initials: KG
authors.lastname: Locke
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Thirumalaichary
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: D G
authors.initials: DG
authors.lastname: Birch
authors.forename: H R
authors.initials: HR
authors.lastname: Vollmer-Snarr
authors.forename: D S
authors.initials: DS
authors.lastname: Williams
authors.forename: K
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism*; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000648:ultrastructure; D012160:Retina / Q000378:metabolism / Q000473:pathology
chemical_list: C418975:ELOVL4 protein, human; C498834:Elovl4 protein, mouse; D005136:Eye Proteins; D008062:Lipofuscin; D008565:Membrane Proteins