The role of ABCR (ABCA4) in photoreceptor cells and Stargardt macular degeneration

  • Robert S. Molday
  • Jinhi Ahn


ATP binding cassette (ABC) transporters are a superfamily of membrane proteins found in virtually all living organisms. They generally function in the active transport of a wide variety of compound s across cell membranes (Higgins 1992; Borst and Elferink 2002). These include amino acids, peptides, ions, metabolites, vitamins, fatty acid derivatives, steroids, organic anions, phospholipids, drugs, and other compounds. ABC transporters typically consist of two membrane domains that provide a pathway for the translocation of a substrate across the membrane and two ATP binding cassettes or nucleo tide binding domains that provide the energy for the substrate transport. These functional domains can exist as individual or multidomain subunits that assemble into an oligomeric complex, or alternatively they all can reside on one large single polypeptide chain (see Chapter 17, Figure 1).


Retinal Pigment Epithelium Retinal Pigment Epithelium Cell Outer Segment Photoreceptor Cell Nucleotide Binding Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahn, J., Wong, J.T., and Molday, R.S. (2000). The Effect of Lipid Environment and Retinoids on the ATPase Activity of ABCR, the Photoreceptor ABC Transporter Responsible for Stargardt Macular Dystrophy. J. Biol. Chem., 275, 20399–20405.PubMedCrossRefGoogle Scholar
  2. Allikmets, R. (2000). Simple and Complex ABCR: Genetic Predisposition to Retinal Disease. Am. J. Hum. Genet., 67, 793–799.PubMedCrossRefGoogle Scholar
  3. Allikmets, R., Shroyer, N.F., Singh, N., Seddon, J.M., Lewis, R.A., Bernstein, P.S., et al. (1997a). Mutation of the Stargardt Disease Gene (ABCR) in Age-Related Macular Degeneration. Science, 277, 1805–1807.PubMedCrossRefGoogle Scholar
  4. Allikmets, R., Singh, N., Sun, H., Shroyer, N.F, Hutchinson, A., Chidambaram, A., et al. (1997b).A Photoreceptor Cell-Specific ATP-Binding Transporter Gene (ABCR) Is Mutated in Recessive Stargardt Macular Dystrophy. (See comments) Nat. Genet., 15, 236–246.PubMedCrossRefGoogle Scholar
  5. Ambudkar, S.V., Lelong, I.H., Zhang, J., Cardarelli, C.O., Gottesman. M.M., and Pastan, I. (1992). Partial Purification and Reconstitution of the Human Multidrug-Resistance Pump: Characterization of the Drug-Stimulatable ATP Hydrolysis. Proc. Natl Acad. Sci. USA, 89, 8472–8476.PubMedCrossRefGoogle Scholar
  6. Anderson, M.P., Gregory, R.J., Thompson, S., Souza, D.W., Paul, S., Mulligan, R.C., et al. (1991). Demonstration that CFTR Is a Chloride Channel by Alteration of its Anion Selectivity. Science, 253, 202–205.PubMedCrossRefGoogle Scholar
  7. Aubourg, P., Mosser, J., Douar, A.M., Sarde, C.O., Lopez, J., and Mandel. J.L. (1993). Adrenoleukodystrophy Gene: Uexpected Homology to a Protein Involved in Peroxisome Biogene sis. Biochimie, 75, 293–302.PubMedCrossRefGoogle Scholar
  8. Azarian, S.M. and Travis, G.H. (1997). The Photoreceptor Rim Protein is an ABC Tran sporter Encoded by the Gene for Recessive Stargardt’ s Disease (ABCR). FEBS Lett., 409, 247–252.PubMedCrossRefGoogle Scholar
  9. Ben-Shabat, S., Parish, C.A., Vollmer, H.R., Itagaki, Y., Fishkin, N., Nakanishi, K., and Sparrow, J.R. (2002). Biosynthetic Studies of A2E, a Major Fluorophore of Retinal Pigment Epithelial Lipofuscin. J. Biol. Chem., 277, 7183–7190.PubMedCrossRefGoogle Scholar
  10. Bok, D. (1993). The Retinal Pigment epithelium: A Versatile Partner in Vision. J. Cell. Sci. Suppl., 17, 189–195.PubMedGoogle Scholar
  11. Borst, P. and Elferink, R.O. (2002). Mammalian ABC Transporters in Health and Disease. Annu. Rev. Biochem., 71, 537–592.PubMedCrossRefGoogle Scholar
  12. Borst, P., Zelcer, N., and van Helvoort, A. (2000). ABC Transporters in Lipid Transport. Biochim. Biophys. Acta, 1486, 128–144.PubMedCrossRefGoogle Scholar
  13. Briggs, C.E., Rucinski, D., Rosenfeld, P.J., Hirose, T., Berson, E.L., and Dryja, T.P. (2001). Mutations in ABCR (ABCA4) in Patient s with Stargardt Macular Degeneration or Cone—Rod Degeneration. Invest. Ophthalmol. Vis. Sci., 42, 2229–2236.PubMedGoogle Scholar
  14. Broccardo, C, Luciani, M., and Chimini, G. (1999). The ABCA Subclass of Mammalian Transporter s. Biochim. Biophys. Acta, 1461, 395–404.PubMedCrossRefGoogle Scholar
  15. Brooks-Wilson, A., Marcil, M., Clee, S.M., Zhang, L.H., Roomp, K., van Dam, M., et al. (1999). Mutations in ABC 1 in Tangier Disease and Familial High-Density Lipoprotein Deficiency. Nat. Genet., 22, 336–345.PubMedCrossRefGoogle Scholar
  16. Buczylko, J., Saari, J.C., Crouch, R.K., and Palczewski, K. (1996). Mechanisms of Opsin Activation. J. Biol. Chem., 271, 20621–20630.PubMedCrossRefGoogle Scholar
  17. Bungert, S., Molday, L.L., and Molday, R.S. (2001). Membrane Topology of the ATP Binding Cassette Transporter ABCR and its Relationship to ABC 1 and Related ABCA Transporters: Identification of N-Linked Glycosylation Sites. J. Biol. Chem., 276, 23539–23546.PubMedCrossRefGoogle Scholar
  18. Cremers, FP., van de Pol, D.J., van Driel, M., den Hollander, A.I., van Haren, F.J., Knoers, N.V., et al. (1998). Autosomal Recessive Retinitis Pigmentosa and Cone-Rod Dystrophy Caused by Splice Site Mutations in the Stargardt’ s Disease Gene ABCR. Hum. Mol. Genet., 7, 355–362.PubMedCrossRefGoogle Scholar
  19. Dean, M. and Allikmets, R. (2001). Complete Characterization of the Human ABC Gene Family. J. Bioenerg. Biomembr., 33, 475–479.PubMedCrossRefGoogle Scholar
  20. Delori, F.C., Staurenghi, G., Arend, O., Dorey, C.K; Goger, D.G., and Weiter, J.J. (1995). In Vivo Measurement of Lipofuscin in Stargardt’s Disease — Fundus Flavirnaculatus. Invest. Ophthalmol. Vis. Sci., 36, 2327–2331.PubMedGoogle Scholar
  21. Delori, F.C., Fleckner, M.R., Goger, D.G., Weiter, J.J., and Dorey, C.K. (2000). Autofluorescence Distribution Associated with Drusen in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci., 41, 496–504.PubMedGoogle Scholar
  22. Dorey, C.K., Wu, G., Eben stein, D., Garsd, A., and Weiter, J.J. (1989). Cell Loss in the Aging Retina. Relationship to Lipofuscin Accumulation and Macular Degeneration. Invest. Ophthalmol. Vis. Sci., 30, 1691–1699.PubMedGoogle Scholar
  23. Eldred, G.E. and Lasky, M.R. (1993). Retinal Age Pigments Generated by Self-Assembling Lysosomotropic Detergents. Nature, 361, 724–726.PubMedCrossRefGoogle Scholar
  24. Feeney-Burns, L., Hilderbrand, E.S., and Eldridge, S. (1984). Aging Human RPE: Morphometric Analysis of Macular, Equatorial, and Peripheral Cells. Invest. Ophthalmol. Vis. Sci., 25, 195–200.PubMedGoogle Scholar
  25. Fitzgerald, M.L., Morris, A.L., Rhee, J.S., Andersson, L.P., Mendez, A.J., and Freeman, M.W. (2002). Naturally Occurring Mutations in the Largest Extracellular Loops of ABCA 1 Can Disrupt its Direct Interaction with Apolipoprotein A-I. J. Biol. Chem., 277, 33178–33187.PubMedCrossRefGoogle Scholar
  26. Franceschetti, A. and Francois, J. (1965). Fundus Flavimaculatus. Arch. Ophthalmol., 25, 505–530.Google Scholar
  27. Gottesman, M.M. and Ambudkar, S.V. (2001). Overview: ABC Transporters and Human Disease. J. Bioenerg. Biomembr., 33, 453–458.Google Scholar
  28. Hettema, E.H. and Tabak, H.F (2000). Transport of Fatty Acids and Metabolites Across the Peroxisomal Membrane. Biochim. Biophys. Acta, 1486, 18–27.PubMedCrossRefGoogle Scholar
  29. Higgins, C.F (1992). ABC Transporters, From Microorganisms to Man. Annu. Rev. Cell. Biol., 8, 67–113.PubMedCrossRefGoogle Scholar
  30. Hipfner, D.R, Deeley, R.G., and Cole, S.P. (1999). Structural, Mechanistic, and Clinical Aspects of MRP 1. Biochim. Biophys. Acta, 1461, 359–376.PubMedCrossRefGoogle Scholar
  31. Holz, F.G., Schutt, E, Kopitz, J., Eldred, G.E., Kruse, FE., Volcker, H.E., et al. (1999). Inhibition of Lysosomal Degradative Functions in RPE Cells by a Retinoid Component of Lipofuscin. Invest. Ophthalmol. Vis. Sci., 40, 737–743.PubMedGoogle Scholar
  32. Illing, M., Molday, L.L., and Molday, R.S. (1997). The 220-kDa Rim Protein of Retinal Rod Outer Segments Is a Member of the ABC Transporter Superfamily. J. Biol. Chem., 272, 10303–10310.PubMedCrossRefGoogle Scholar
  33. Juranka, P.F., Zastawny, R.L., and Ling, V. (1989). Pglycoprotein: Multidrug-Resistance and a Superfamily of Membrane-Associated Transport Proteins. FASEB J., 3, 2583–2592.PubMedGoogle Scholar
  34. Kennedy, C.J., Rakoczy, P.E., and Constable, I.J (1995). Lipofuscin of the Retinal Pigment Epithelium: A Review. Eye, 9, 763–771.PubMedCrossRefGoogle Scholar
  35. Klein, B.A. and Krill, A.E. (1967). Fundus Flavimaculatus: Clinical, Functional and Histopathologic Observations. Am. J. Ophthalmol., 64, 3–23.Google Scholar
  36. Lewis, RA., Shroyer, N.F., Singh, N., Allikmets, R., Hutchinson, A., Li, Y., et al. (1999). Genotype/ Phenotype Analysis of a Photoreceptor-Specific ATPBinding Cassette Transporter Gene, ABCR, in Stargardt Disease. Am. J. Hum. Genet., 64, 422–434.PubMedCrossRefGoogle Scholar
  37. Martinez-Mir, A., Paloma, E., AlIikmets, R., Ayuso, C., del Rio, T., Dean, M., et al. (1998). Retinitis Pigmentosa Caused by a Homozygous Mutation in the Stargardt Disease Gene ABCR Nat. Genet., 18, 11–12.PubMedCrossRefGoogle Scholar
  38. Mata, N.L., Weng, J., and Travis, G.H. (2000). Biosynthesis of a Major Lipofuscin Fluorophore in Mice and Humans with ABCR-Mediated Retinal and Macular Degeneration. Proc. Natl Acad. Sci. USA, 97, 7154–7159.PubMedCrossRefGoogle Scholar
  39. Mata, N.L., Tzekov, R.T, Liu, X., Weng, J., Birch, D.G., and Travis, G.H. (2001). Delayed Dark-Adaptation and Lipofuscin Accumulation in abcr +/-Mice: Implications for Involvement of ABCR in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci., 42, 1685–1690.PubMedGoogle Scholar
  40. Maugeri, A., van Driel, M.A., van de Pol, D.J., Klevering, B.J., van Haren, F.J., Tijmes, N., et al. (1999). The 2588G>C Mutation in the ABCR Gene is a Mild Frequent Founder Mutation in the Western European Population and Allows the Classification of ABCR Mutations in Patients with Stargardt Disease. Am. J. Hum. Genet., 64, 1024–1035.PubMedCrossRefGoogle Scholar
  41. Maugeri, A., Klevering, B.J., Rohrschneider, K., Blankenagel, A., Brunner, H.G., Deutman, A.E, et al. (2000). Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy. Am. J. Hum. Genet., 67, 960–966.PubMedCrossRefGoogle Scholar
  42. McBee, J.K., Palczewski, K., Baehr, w., and Pepperberg, D.R. (2001). Confronting Complexity: The Interlink of Phototransduction and Retinoid Metabolism in the Vertebrate Retina. Prog. Retin. Eye. Res., 20, 469–529.PubMedCrossRefGoogle Scholar
  43. Molday, R.S. (1998). Photoreceptor Membrane Proteins, Phototransduction, and Retinal Degenerative Diseases. The Friedenwald Lecture. Invest. Ophthalmol. Vis. Sci., 39, 2491–2513.PubMedGoogle Scholar
  44. Molday, L.L., Rabin, A.R., and Molday, R.S. (2000). ABCR expression in Foveal Cone Photoreceptors and its Role in Stargardt Macular Dystrophy. Nat. Genet., 25, 257–258.PubMedCrossRefGoogle Scholar
  45. Monaco, J.J., Cho, S., and Attaya, M. (1990). Transport Protein Genes in the Murine MHC: Possible Implications for Antigen Processing. Science, 250, 1723–1726PubMedCrossRefGoogle Scholar
  46. Nasonkin, I., Illing, M., Koehler, M.R., Schmid, M., Molday, R.S., and Weber, B.H. (1998). Mapping of the Rod Photoreceptor ABC Transporter (ABCR) to Ip21-p22. 1 and Identification of Novel Mutations in Stargardt’s Disease. Hum. Genet., 102, 21–26.PubMedCrossRefGoogle Scholar
  47. Oram, J.F (2002). ATP-Binding Cassette Transporter Al and Cholesterol Trafficking. Curr. Opin. Lipidol., 13, 373–381.PubMedCrossRefGoogle Scholar
  48. Palczewski, K., Van Hooser, J.P., Garwin, G.G., Chen, J., Liou, G.I., and Saari, J.C. (1999). Kinetics of Visual Pigment Regeneration in Excised Mouse Eyes and in Mice with a Targeted Disruption of the Gene Encoding Interphotoreceptor Retinoid-Binding Protein or Arrestin. Biochemistry, 38, 12012–12019.PubMedCrossRefGoogle Scholar
  49. Papaioannou, M., Ocaka, L., Bessant, D., Lois, N., Bird, A., Payne, A., et al. (2000). An Analysis of ABCR Mutations in British Patients with Recessive Retinal Dystrophies. Invest. Ophthalmol. Vis. Sci., 41, 16–19.PubMedGoogle Scholar
  50. Papermaster, D.S., Schneider, B.G., Zorn, M.A., and Kraehenbuhl, J.P. (1978). Immunocytochemical Localization of a Large Intrinsic Membrane Protein to the Incisures and Margins of Frog Rod Outer Segment Disks. J. Cell Biol., 78, 415–425.PubMedCrossRefGoogle Scholar
  51. Papermaster, D.S., Reilly, P., and Schneider, E.G. (1982). Cone Lamellae and Red and Green Rod Outer Segment Disks Contain a Large Intrinsic Membrane Protein on their Margins: An Ultrastructural Immunocytochemical Study of Frog Retinas. Vision Res., 22, 1417–1428.PubMedCrossRefGoogle Scholar
  52. Parish, C.A., Hashimoto, M., Nakanishi, K., Dillon, J., and Sparrow, J. (1998). Isolation and One-Step Preparation of A2E and Iso-A2E, Fluorophores from Human Retinal Pigment Epithelium. Proc. Natl Acad. Sci. USA, 95, 14609–14613.PubMedCrossRefGoogle Scholar
  53. Poincelot, R.P., Millar, P.G., Kimbel, R.L., and Abrahamson, E.W. (1969). Lipid to Protein Chromophore Transfer in the Photolysis of Visual Pigments. Nature, 221, 256–257.PubMedCrossRefGoogle Scholar
  54. Rivera, A., White, K., Stohr, H., Steiner, K., Hemmrich, N., Grimm, T, et al. (2000). A Comprehensive Survey of Sequence Variation in the ABCA4 (ABCR) Gene in Stargardt Disease and Age-Related Macular Degeneration. Am. J. Hum. Genet., 67, 800–813.PubMedCrossRefGoogle Scholar
  55. Rozet, J.M., Gerber, S., Souied, E., Perrault, I., Chatelin, S., Ghazi, I., et al. (1998). Spectrum of ABCR Gene Mutations in Autosomal Recessive Macular Dystrophies. Eur.J. Hum. Genet., 6, 291–295.PubMedCrossRefGoogle Scholar
  56. Rozet, J.M., Gerber, S., Souied, E., Ducroq, D., Perrault, I., Ghazi, I., et al. (1999). The ABCR Gene: A Major Disease Gene in Macular and Peripheral Retinal Degenerations with Onset from Early Childhood to the Elderly. Mol. Genet. Metab., 68, 310–315.PubMedCrossRefGoogle Scholar
  57. Saari, J.C. (2000) Biochemistry of Visual Pigment Regeneration: The Friedenwald Lecture. Invest. Ophthalmol. Vis. Sci., 41, 337–348.PubMedGoogle Scholar
  58. Saari, J.C., Garwin, G.G., van Hooser, J. P., and Palczewski, K. (1998). Reduction of all-trans Retinal Limits Regeneration of Visual Pigment in Mice. Vision Res., 38, 1325–1333.PubMedCrossRefGoogle Scholar
  59. Sakai, N., Decatur, J., Nakanishi, K., and Eldred, G.E. (1996). Ocular Age Pigment “A2-E”: An Unprecented Pyridinium Bisretinoid. J. Am. Chem. Soc., 118, 1559–1560.CrossRefGoogle Scholar
  60. Shapiro, A.B. and Ling, V. (1994). ATPase Activity of Purified and Reconstituted P-Glycoprotein from Chinese Hamster Ovary Cells. J. Biol. Chem., 269, 3745–3754.PubMedGoogle Scholar
  61. Sparrow, J.R., Nakanishi, K., and Parish, C.A. (2000). The Lipofuscin Fluorophore A2E Mediates Blue Light-Induced Damage to Retinal Pigmented Epithelial Cells. Invest. Ophthalmol. Vis. Sci., 41, 1981–1989.PubMedGoogle Scholar
  62. Stargardt, K. (1909). Über Familiare, Progressiv Degeneration under Makulagegend des Augen. Alhrecht von Graefes Arch. Klin Exp Ophthalmol., 71, 534–550.Google Scholar
  63. Sun, H. and Nathans, J. (2001). Mechanistic Studies of ABCR, the ABC Transporter in Photoreceptor Outer Segments Responsible for Autosomal Recessive Stargardt Disease. J. Bioenerg. Biomembr., 33, 523–530.PubMedCrossRefGoogle Scholar
  64. Sun, H. and Nathan S, J. (1997). Stargardt’s ABCR is Localized to the Disc Membrane of Retinal Rod Outer Segments (Letter). Nat. Genet., 17, 15–16.PubMedCrossRefGoogle Scholar
  65. Sun, H., Molday, R.S., and Nathans, J. (1999). Retinal Stimulates ATP Hydrolysis by Purified and Reconstituted ABCR, the Photoreceptor-Specific ATPBinding Cassette Transporter Responsible for Stargardt Disease. J. Biol. Chem., 274, 8269–8281.PubMedCrossRefGoogle Scholar
  66. Sun, H., Smallwood, P.M., and Nathans, J. (2000). Biochemical Defects in ABCR Protein Variants Associated with Human Retinopathies. Nat. Genet., 26, 242–246.PubMedCrossRefGoogle Scholar
  67. Surya, A. and Knox, B.E. (1998). Enhancement of Opsin Activity by all-trans Retinal. Exp. Eye Res., 66, 599–603.PubMedCrossRefGoogle Scholar
  68. van Driel, M.A., Maugeri, A., Klevering, B.J., Hoyng, C.B., and Cremers, F.P. (1998). ABCR Unites what Ophthalmologists Divide(s). Ophthalmic Genet., 19, 117–122.PubMedCrossRefGoogle Scholar
  69. Wang, N., Silver, D.L., Thiele, C., and Tall, A.R. (2001). ATP-Binding Cassette Transporter A 1 (ABCA 1) Functions as a Cholesterol Efflux Regulatory Protein. J. Biol. Chem., 276, 23742–23747.PubMedCrossRefGoogle Scholar
  70. Webster, A.R., Heon, E., Lotery, A.J., Vandenburgh, K., Casavant, T.L., Oh, K.T., et al. (2001). An Analysis of Allelic Variation in the ABCA4 Gene. Invest. Ophthalmol. Vis. Sci., 42, 1179–1189.PubMedGoogle Scholar
  71. Weleber, R.G. (1994). Stargardr’s Macular Dystrophy. Arch. Ophthalmol., 112, 752–754.PubMedCrossRefGoogle Scholar
  72. Weng, J., Mata, N.L., Azarian, S.M., Tzekov, R.T., Birch, D.G., and Travis, G.H. (1999). Insights into the Function of Rim Protein in Photoreceptors and Etiology of Stargardt’ s Disease from the Phenotype in abcr Knockout Mice. Cell, 98, 13–23.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Robert S. Molday
    • 1
  • Jinhi Ahn
    • 1
  1. 1.Biochemistry and Molecular Biology, Faculty of MedicineUniversity of British ColumbiaVancouverCanada

Personalised recommendations