Lipofuscin Accumulation, Abnormal Electrophysiology, and Photoreceptor Degeneration in Mutant ELOVL4 Transgenic Mice: A Model for Macular Degeneration

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 t...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 11; pp. 4164 - 4169
Main Authors Karan, G., Lillo, C., Yang, Z., Cameron, D. J., Locke, K. G., Zhao, Y., Thirumalaichary, S., Li, C., Birch, D. G., Vollmer-Snarr, H. R., Williams, D. S., Zhang, K., Nathans, Jeremy
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 15.03.2005
National Acad Sciences
Subjects
Animals
Biological Sciences
Complementary DNA
Disease Models, Animal
Electrophysiology
Eye Proteins - genetics
Eye Proteins - metabolism
Fatty acids
Gene expression
Humans
Isomers
Lipofuscin - metabolism
Macular degeneration
Macular Degeneration - genetics
Macular Degeneration - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Transgenic
Microscopy, Electron
Mutation
Neurology
Photoreceptor Cells - metabolism
Photoreceptor Cells - ultrastructure
Photoreceptors
Polymerase chain reaction
Retina
Retina - metabolism
Retina - pathology
Reverse transcriptase polymerase chain reaction
Transgenes
Transgenic animals
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Summary: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.
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To whom correspondence may be addressed. E-mail: kang.zhang@hmbg.utah.edu, dswilliams@ucsd.edu, or hrvs@chem.byu.edu.
This paper was submitted directly (Track II) to the PNAS office.
Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 27, 2005
Author contributions: D.S.W., D.G.B., H.V.R.S., and K.Z. designed research; G.K., C. Lillo, Z.Y., D.J.C., K.G.L., Y.Z., C. Li, and K.Z. performed research; G.K., C. Lillo, Z.Y., D.J.C., K.G.L., Y.Z., D.S.W., and K.Z. analyzed data; G.K., D.G.B., D.S.W., H.V.R.S., and K.Z. wrote the paper; and G.K., D.G.B., D.S.W., D.J.C., and K.Z. edited photomicrographs.
G.K., C.L., Z.Y., and D.J.C. contributed equally to this work.
Abbreviations: AMD, age-related macular degeneration; STGD, Stargardt macular dystrophy; RPE, retinal pigment epithelium; IRBP, interphotoreceptor retinoid-binding protein; ERG, electroretinography; A2E, 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407698102