| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 From the Jules Stein Eye Institute, University of California, Los Angeles; 2 Department of Ophthalmology, Stanford University; 3 Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas; 4 Retina Foundation of the Southwest, Dallas; and 5 Department of Biological Chemistry, University of California, Los Angeles.
PURPOSE. To examine the ocular phenotype in mice heterozygous for a null mutation in the abcr gene.
METHODS. Retinas and retinal pigment epithelia (RPE) were prepared from wild-type, abcr+/-, and abcr-/- mice. Fresh tissues were homogenized and analyzed by normal phase high-performance liquid chromatography (HPLC) for the presence of retinoids and phospholipids. In another study, fixed tissues were sectioned and analyzed by light and electron microscopy. Finally, anesthetized mice were studied by electroretinography (ERG) at different times after exposure to strong light.
RESULTS. A2E, the major fluorophore of lipofuscin, and its precursors, A2PE-H2 and A2PE, were approximately fourfold more abundant in 8-month-old abcr+/- than in the wild-type retina and RPE. The levels of these substances in abcr+/- mice were approximately 40% those in abcr-/- mice. Lipofuscin pigment-granules were also visible in abcr+/- RPE cells by electron microscopy. Accumulation of A2PE-H2 and A2E in abcr+/- retina and RPE, respectively, was strongly dependent on light exposure. Heterozygous mutants also exhibited delayed recovery of rod sensitivity by ERG. This delay was correlated with elevated levels of all-trans-retinaldehyde (all-trans-RAL) in retina after a photobleach and was not caused by a reduction in quantum-catch due to depletion of 11-cis-retinaldehyde (11-cis-RAL).
CONCLUSIONS. Partial loss of the ABCR or rim protein is sufficient to cause a phenotype in mice similar to recessive Stargardt’s disease (STGD) and age-related macular degeneration (AMD) in humans. These data are consistent with the suggestion that the STGD carrier-state may predispose to the development of AMD.
This article has been cited by other articles:
|
|
 |
|
  H. F. Edelhauser, J. H. Boatright, J. M. Nickerson, and the Third ARVO/Pfizer Research Institute Working G Drug Delivery to Posterior Intraocular Tissues: Third Annual ARVO/Pfizer Ophthalmics Research Institute Conference Invest. Ophthalmol. Vis. Sci., November 1, 2008; 49(11): 4712 - 4720. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maeda, T. Maeda, M. Golczak, and K. Palczewski Retinopathy in Mice Induced by Disrupted All-trans-retinal Clearance J. Biol. Chem., September 26, 2008; 283(39): 26684 - 26693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Radu, Q. Yuan, J. Hu, J. H. Peng, M. Lloyd, S. Nusinowitz, D. Bok, and G. H. Travis Accelerated Accumulation of Lipofuscin Pigments in the RPE of a Mouse Model for ABCA4-Mediated Retinal Dystrophies following Vitamin A Supplementation Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 3821 - 3829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Pawar, N. M. Qtaishat, D. M. Little, and D. R. Pepperberg Recovery of Rod Photoresponses in ABCR-Deficient Mice Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2743 - 2755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Maia-Lopes, E. D. Silva, M. F. Silva, A. Reis, P. Faria, and M. Castelo-Branco Evidence of Widespread Retinal Dysfunction in Patients with Stargardt Disease and Morphologically Unaffected Carrier Relatives Invest. Ophthalmol. Vis. Sci., March 1, 2008; 49(3): 1191 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maeda, T. Maeda, W. Sun, H. Zhang, W. Baehr, and K. Palczewski Redundant and unique roles of retinol dehydrogenases in the mouse retina PNAS, December 4, 2007; 104(49): 19565 - 19570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tuo, C. M. Bojanowski, M. Zhou, D. Shen, R. J. Ross, K. I. Rosenberg, D. J. Cameron, C. Yin, J. A. Kowalak, Z. Zhuang, et al. Murine Ccl2/Cx3cr1 Deficiency Results in Retinal Lesions Mimicking Human Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3827 - 3836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maeda, T. Maeda, Y. Imanishi, W. Sun, B. Jastrzebska, D. A. Hatala, H. J. Winkens, K. P. Hofmann, J. J. Janssen, W. Baehr, et al. Retinol Dehydrogenase (RDH12) Protects Photoreceptors from Light-induced Degeneration in Mice J. Biol. Chem., December 8, 2006; 281(49): 37697 - 37704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Vasireddy, M. M. Jablonski, M. N. A. Mandal, D. Raz-Prag, X. F. Wang, L. Nizol, A. Iannaccone, D. C. Musch, R. A. Bush, N. Salem Jr, et al. Elovl4 5-bp-Deletion Knock-in Mice Develop Progressive Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4558 - 4568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maeda, T. Maeda, M. Golczak, Y. Imanishi, P. Leahy, R. Kubota, and K. Palczewski Effects of Potent Inhibitors of the Retinoid Cycle on Visual Function and Photoreceptor Protection from Light Damage in Mice Mol. Pharmacol., October 1, 2006; 70(4): 1220 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D M Paskowitz, M M LaVail, and J L Duncan Light and inherited retinal degeneration Br. J. Ophthalmol., August 1, 2006; 90(8): 1060 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V. Bui, Y. Han, R. A. Radu, G. H. Travis, and N. L. Mata Characterization of Native Retinal Fluorophores Involved in Biosynthesis of A2E and Lipofuscin-associated Retinopathies J. Biol. Chem., June 30, 2006; 281(26): 18112 - 18119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Radu, Y. Han, T. V. Bui, S. Nusinowitz, D. Bok, J. Lichter, K. Widder, G. H. Travis, and N. L. Mata Reductions in Serum Vitamin A Arrest Accumulation of Toxic Retinal Fluorophores: A Potential Therapy for Treatment of Lipofuscin-Based Retinal Diseases Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4393 - 4401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hargitai, J. Zernant, G. M. Somfai, R. Vamos, A. Farkas, G. Salacz, and R. Allikmets Correlation of Clinical and Genetic Findings in Hungarian Patients with Stargardt Disease Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4402 - 4408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Wiszniewski, C. M. Zaremba, A. N. Yatsenko, M. Jamrich, T. G. Wensel, R. A. Lewis, and J. R. Lupski ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies Hum. Mol. Genet., October 1, 2005; 14(19): 2769 - 2778. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bindewald, A. C. Bird, S. S. Dandekar, J. Dolar-Szczasny, J. Dreyhaupt, F. W. Fitzke, W. Einbock, F. G. Holz, J. J. Jorzik, C. Keilhauer, et al. Classification of Fundus Autofluorescence Patterns in Early Age-Related Macular Disease Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3309 - 3314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Fishkin, J. R. Sparrow, R. Allikmets, and K. Nakanishi Isolation and characterization of a retinal pigment epithelial cell fluorophore: An all-trans-retinal dimer conjugate PNAS, May 17, 2005; 102(20): 7091 - 7096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ding, M. Scortegagna, R. Seaman, D. G. Birch, and J. A. Garcia Retinal Disease in Mice Lacking Hypoxia-Inducible Transcription Factor-2{alpha} Invest. Ophthalmol. Vis. Sci., March 1, 2005; 46(3): 1010 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Beharry, M. Zhong, and R. S. Molday N-Retinylidene-phosphatidylethanolamine Is the Preferred Retinoid Substrate for the Photoreceptor-specific ABC Transporter ABCA4 (ABCR) J. Biol. Chem., December 24, 2004; 279(52): 53972 - 53979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Howes, Y. Liu, J. L. Dunaief, A. Milam, J. M. Frederick, A. Marks, and W. Baehr Receptor for Advanced Glycation End Products and Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3713 - 3720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Kim, N. Fishkin, J. Kong, K. Nakanishi, R. Allikmets, and J. R. Sparrow Rpe65 Leu450Met variant is associated with reduced levels of the retinal pigment epithelium lipofuscin fluorophores A2E and iso-A2E PNAS, August 10, 2004; 101(32): 11668 - 11672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Gao and P. Talalay Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage PNAS, July 13, 2004; 101(28): 10446 - 10451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Radu, N. L. Mata, A. Bagla, and G. H. Travis Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration PNAS, April 20, 2004; 101(16): 5928 - 5933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shulenin, L. M. Nogee, T. Annilo, S. E. Wert, J. A. Whitsett, and M. Dean ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency N. Engl. J. Med., March 25, 2004; 350(13): 1296 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Cideciyan, T. S. Aleman, M. Swider, S. B. Schwartz, J. D. Steinberg, A. J. Brucker, A. M. Maguire, J. Bennett, E. M. Stone, and S. G. Jacobson Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence Hum. Mol. Genet., March 1, 2004; 13(5): 525 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Michaelides, D M Hunt, and A T Moore The genetics of inherited macular dystrophies J. Med. Genet., September 1, 2003; 40(9): 641 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schmidt, E. A. Postel, A. Agarwal, I. C. Allen Jr, S. N. Walters, M. A. De La Paz, W. K. Scott, J. L. Haines, M. A. Pericak-Vance, and J. R. Gilbert Detailed Analysis of Allelic Variation in the ABCA4 Gene in Age-Related Maculopathy Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2868 - 2875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Cox, R. M. Hansen, N. Quinn, and A. B. Fulton Retinal Function in Carriers of Bardet-Biedl Syndrome Arch Ophthalmol, June 1, 2003; 121(6): 804 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Sparrow, J. Zhou, and B. Cai DNA Is a Target of the Photodynamic Effects Elicited in A2E-Laden RPE by Blue-Light Illumination Invest. Ophthalmol. Vis. Sci., May 1, 2003; 44(5): 2245 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Radu, N. L. Mata, S. Nusinowitz, X. Liu, P. A. Sieving, and G. H. Travis From the Cover: Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration PNAS, April 15, 2003; 100(8): 4742 - 4747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Rakoczy, D. Zhang, T. Robertson, N. L. Barnett, J. Papadimitriou, I. J. Constable, and C.-M. Lai Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model Am. J. Pathol., October 1, 2002; 161(4): 1515 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Parisi, D. Canu, G. Iarossi, D. Olzi, and B. Falsini Altered Recovery of Macular Function after Bleaching in Stargardt's Disease-Fundus Flavimaculatus: Pattern VEP Evidence Invest. Ophthalmol. Vis. Sci., August 1, 2002; 43(8): 2741 - 2748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. De and T. P. Sakmar Interaction of A2E with Model Membranes. Implications to the Pathogenesis of Age-related Macular Degeneration J. Gen. Physiol., July 30, 2002; 120(2): 147 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Bernstein, M. Leppert, N. Singh, M. Dean, R. A. Lewis, J. R. Lupski, R. Allikmets, and J. M. Seddon Genotype-Phenotype Analysis of ABCR Variants in Macular Degeneration Probands and Siblings Invest. Ophthalmol. Vis. Sci., February 1, 2002; 43(2): 466 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Gao, A. Wenzel, C. Grimm, S. R. Vavricka, D. Benke, P. J. Meier, and C. E. Reme Localization of Organic Anion Transport Protein 2 in the Apical Region of Rat Retinal Pigment Epithelium Invest. Ophthalmol. Vis. Sci., February 1, 2002; 43(2): 510 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. F. Shroyer, R. A. Lewis, A. N. Yatsenko, T. G. Wensel, and J. R. Lupski Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration Hum. Mol. Genet., November 1, 2001; 10(23): 2671 - 2678. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
