Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2003 Sep;40(9):641–650. doi: 10.1136/jmg.40.9.641

The genetics of inherited macular dystrophies

M Michaelides 1, D Hunt 1, A Moore 1
PMCID: PMC1735576  PMID: 12960208

Abstract

The aim of this paper is to review current knowledge relating to the monogenic macular dystrophies, with discussion of currently mapped genes, chromosomal loci and genotype-phenotype relationships. Inherited systemic disorders with a macular dystrophy component will not be discussed.

Full Text

The Full Text of this article is available as a PDF (2.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali R. R., Sarra G. M., Stephens C., Alwis M. D., Bainbridge J. W., Munro P. M., Fauser S., Reichel M. B., Kinnon C., Hunt D. M. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet. 2000 Jul;25(3):306–310. doi: 10.1038/77068. [DOI] [PubMed] [Google Scholar]
  2. Allikmets R., Shroyer N. F., Singh N., Seddon J. M., Lewis R. A., Bernstein P. S., Peiffer A., Zabriskie N. A., Li Y., Hutchinson A. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805–1807. doi: 10.1126/science.277.5333.1805. [DOI] [PubMed] [Google Scholar]
  3. Allikmets R., Singh N., Sun H., Shroyer N. F., Hutchinson A., Chidambaram A., Gerrard B., Baird L., Stauffer D., Peiffer A. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 Mar;15(3):236–246. doi: 10.1038/ng0397-236. [DOI] [PubMed] [Google Scholar]
  4. Berninger T. A., Polkinghorne P. J., Capon M. R., Arden G. B., Bird A. C. Farbsinnstörung. Ein Frühzeichen bei Sorsby-Netzhautdystrophie? Ophthalmologe. 1993 Oct;90(5):515–518. [PubMed] [Google Scholar]
  5. Bernstein P. S., Tammur J., Singh N., Hutchinson A., Dixon M., Pappas C. M., Zabriskie N. A., Zhang K., Petrukhin K., Leppert M. Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3331–3336. [PubMed] [Google Scholar]
  6. Birnbach C. D., Järveläinen M., Possin D. E., Milam A. H. Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus. Ophthalmology. 1994 Jul;101(7):1211–1219. doi: 10.1016/s0161-6420(13)31725-4. [DOI] [PubMed] [Google Scholar]
  7. Brecher R., Bird A. C. Adult vitelliform macular dystrophy. Eye (Lond) 1990;4(Pt 1):210–215. doi: 10.1038/eye.1990.28. [DOI] [PubMed] [Google Scholar]
  8. Caldwell G. M., Kakuk L. E., Griesinger I. B., Simpson S. A., Nowak N. J., Small K. W., Maumenee I. H., Rosenfeld P. J., Sieving P. A., Shows T. B. Bestrophin gene mutations in patients with Best vitelliform macular dystrophy. Genomics. 1999 May 15;58(1):98–101. doi: 10.1006/geno.1999.5808. [DOI] [PubMed] [Google Scholar]
  9. Capon M. R., Marshall J., Krafft J. I., Alexander R. A., Hiscott P. S., Bird A. C. Sorsby's fundus dystrophy. A light and electron microscopic study. Ophthalmology. 1989 Dec;96(12):1769–1777. doi: 10.1016/s0161-6420(89)32664-9. [DOI] [PubMed] [Google Scholar]
  10. Chong N. H., Alexander R. A., Gin T., Bird A. C., Luthert P. J. TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy. Invest Ophthalmol Vis Sci. 2000 Mar;41(3):898–902. [PubMed] [Google Scholar]
  11. Cremers F. P., van de Pol D. J., van Driel M., den Hollander A. I., van Haren F. J., Knoers N. V., Tijmes N., Bergen A. A., Rohrschneider K., Blankenagel A. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. Hum Mol Genet. 1998 Mar;7(3):355–362. doi: 10.1093/hmg/7.3.355. [DOI] [PubMed] [Google Scholar]
  12. De La Paz M. A., Guy V. K., Abou-Donia S., Heinis R., Bracken B., Vance J. M., Gilbert J. R., Gass J. D., Haines J. L., Pericak-Vance M. A. Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration. Ophthalmology. 1999 Aug;106(8):1531–1536. doi: 10.1016/S0161-6420(99)90449-9. [DOI] [PubMed] [Google Scholar]
  13. Deutman A. F. Electro-oculography in families with vitelliform dystrophy of the fovea. Detection of the carrier state. Arch Ophthalmol. 1969 Mar;81(3):305–316. doi: 10.1001/archopht.1969.00990010307001. [DOI] [PubMed] [Google Scholar]
  14. Deutman A. F., Pinckers A. J., Aan de Kerk A. L. Dominantly inherited cystoid macular edema. Am J Ophthalmol. 1976 Oct;82(4):540–548. doi: 10.1016/0002-9394(76)90540-7. [DOI] [PubMed] [Google Scholar]
  15. Donoso L. A., Edwards A. O., Frost A., Vrabec T., Stone E. M., Hageman G. S., Perski T. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol. 2001 Sep-Oct;46(2):149–163. doi: 10.1016/s0039-6257(01)00251-x. [DOI] [PubMed] [Google Scholar]
  16. Dorey C. K., Wu G., Ebenstein D., Garsd A., Weiter J. J. Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci. 1989 Aug;30(8):1691–1699. [PubMed] [Google Scholar]
  17. Douglas A. A., Waheed I., Wyse C. T. Progressive bifocal chorio-retinal atrophy. A rare familial disease of the eyes. Br J Ophthalmol. 1968 Oct;52(10):742–751. doi: 10.1136/bjo.52.10.742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Downes S. M., Fitzke F. W., Holder G. E., Payne A. M., Bessant D. A., Bhattacharya S. S., Bird A. C. Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families. Arch Ophthalmol. 1999 Oct;117(10):1373–1383. doi: 10.1001/archopht.117.10.1373. [DOI] [PubMed] [Google Scholar]
  19. Eagle R. C., Jr, Lucier A. C., Bernardino V. B., Jr, Yanoff M. Retinal pigment epithelial abnormalities in fundus flavimaculatus: a light and electron microscopic study. Ophthalmology. 1980 Dec;87(12):1189–1200. doi: 10.1016/s0161-6420(80)35106-3. [DOI] [PubMed] [Google Scholar]
  20. Eksandh L. C., Ponjavic V., Ayyagari R., Bingham E. L., Hiriyanna K. T., Andréasson S., Ehinger B., Sieving P. A. Phenotypic expression of juvenile X-linked retinoschisis in Swedish families with different mutations in the XLRS1 gene. Arch Ophthalmol. 2000 Aug;118(8):1098–1104. doi: 10.1001/archopht.118.8.1098. [DOI] [PubMed] [Google Scholar]
  21. Farrar G. J., Kenna P., Jordan S. A., Kumar-Singh R., Humphries M. M., Sharp E. M., Sheils D. M., Humphries P. A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature. 1991 Dec 12;354(6353):478–480. doi: 10.1038/354478a0. [DOI] [PubMed] [Google Scholar]
  22. Felbor U., Schilling H., Weber B. H. Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene. Hum Mutat. 1997;10(4):301–309. doi: 10.1002/(SICI)1098-1004(1997)10:4<301::AID-HUMU6>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  23. Felbor U., Stöhr H., Amann T., Schönherr U., Weber B. H. A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features. Hum Mol Genet. 1995 Dec;4(12):2415–2416. doi: 10.1093/hmg/4.12.2415. [DOI] [PubMed] [Google Scholar]
  24. Fish G., Grey R., Sehmi K. S., Bird A. C. The dark choroid in posterior retinal dystrophies. Br J Ophthalmol. 1981 May;65(5):359–363. doi: 10.1136/bjo.65.5.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fisher S. K., Stone J., Rex T. S., Linberg K. A., Lewis G. P. Experimental retinal detachment: a paradigm for understanding the effects of induced photoreceptor degeneration. Prog Brain Res. 2001;131:679–698. doi: 10.1016/s0079-6123(01)31053-1. [DOI] [PubMed] [Google Scholar]
  26. Fishman G. A., Farber M., Patel B. S., Derlacki D. J. Visual acuity loss in patients with Stargardt's macular dystrophy. Ophthalmology. 1987 Jul;94(7):809–814. doi: 10.1016/s0161-6420(87)33533-x. [DOI] [PubMed] [Google Scholar]
  27. Fishman G. A., Farbman J. S., Alexander K. R. Delayed rod dark adaptation in patients with Stargardt's disease. Ophthalmology. 1991 Jun;98(6):957–962. doi: 10.1016/s0161-6420(91)32196-1. [DOI] [PubMed] [Google Scholar]
  28. Forsman K., Graff C., Nordström S., Johansson K., Westermark E., Lundgren E., Gustavson K. H., Wadelius C., Holmgren G. The gene for Best's macular dystrophy is located at 11q13 in a Swedish family. Clin Genet. 1992 Sep;42(3):156–159. doi: 10.1111/j.1399-0004.1992.tb03229.x. [DOI] [PubMed] [Google Scholar]
  29. Francis P. J., Johnson S., Edmunds B., Kelsell R. E., Sheridan E., Garrett C., Holder G. E., Hunt D. M., Moore A. T. Genetic linkage analysis of a novel syndrome comprising North Carolina-like macular dystrophy and progressive sensorineural hearing loss. Br J Ophthalmol. 2003 Jul;87(7):893–898. doi: 10.1136/bjo.87.7.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Frangieh G. T., Green W. R., Fine S. L. A histopathologic study of Best's macular dystrophy. Arch Ophthalmol. 1982 Jul;100(7):1115–1121. doi: 10.1001/archopht.1982.01030040093017. [DOI] [PubMed] [Google Scholar]
  31. George N. D., Yates J. R., Bradshaw K., Moore A. T. Infantile presentation of X linked retinoschisis. Br J Ophthalmol. 1995 Jul;79(7):653–657. doi: 10.1136/bjo.79.7.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. George N. D., Yates J. R., Moore A. T. X linked retinoschisis. Br J Ophthalmol. 1995 Jul;79(7):697–702. doi: 10.1136/bjo.79.7.697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Gerth Christina, Andrassi-Darida Monika, Bock Markus, Preising Markus N., Weber Bernhard H. F., Lorenz Birgit. Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. Graefes Arch Clin Exp Ophthalmol. 2002 Jul 4;240(8):628–638. doi: 10.1007/s00417-002-0502-y. [DOI] [PubMed] [Google Scholar]
  34. Godley B. F., Tiffin P. A., Evans K., Kelsell R. E., Hunt D. M., Bird A. C. Clinical features of progressive bifocal chorioretinal atrophy: a retinal dystrophy linked to chromosome 6q. Ophthalmology. 1996 Jun;103(6):893–898. doi: 10.1016/s0161-6420(96)30590-3. [DOI] [PubMed] [Google Scholar]
  35. Goto Y., Nonaka I., Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990 Dec 13;348(6302):651–653. doi: 10.1038/348651a0. [DOI] [PubMed] [Google Scholar]
  36. Grayson C., Reid S. N., Ellis J. A., Rutherford A., Sowden J. C., Yates J. R., Farber D. B., Trump D. Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells. Hum Mol Genet. 2000 Jul 22;9(12):1873–1879. doi: 10.1093/hmg/9.12.1873. [DOI] [PubMed] [Google Scholar]
  37. Griesinger I. B., Sieving P. A., Ayyagari R. Autosomal dominant macular atrophy at 6q14 excludes CORD7 and MCDR1/PBCRA loci. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):248–255. [PubMed] [Google Scholar]
  38. Hamdi Hamdi K., Reznik Jacob, Castellon Raquel, Atilano Shari R., Ong John M., Udar Nitin, Tavis Jeffrey H., Aoki Annette M., Nesburn Anthony B., Boyer David S. Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration. Biochem Biophys Res Commun. 2002 Jul 19;295(3):668–672. doi: 10.1016/s0006-291x(02)00728-3. [DOI] [PubMed] [Google Scholar]
  39. Hoyng C. B., Deutman A. F. The development of central areolar choroidal dystrophy. Graefes Arch Clin Exp Ophthalmol. 1996 Feb;234(2):87–93. doi: 10.1007/BF00695246. [DOI] [PubMed] [Google Scholar]
  40. Hoyng C. B., Heutink P., Testers L., Pinckers A., Deutman A. F., Oostra B. A. Autosomal dominant central areolar choroidal dystrophy caused by a mutation in codon 142 in the peripherin/RDS gene. Am J Ophthalmol. 1996 Jun;121(6):623–629. doi: 10.1016/s0002-9394(14)70627-0. [DOI] [PubMed] [Google Scholar]
  41. Hughes A. E., Lotery A. J., Silvestri G. Fine localisation of the gene for central areolar choroidal dystrophy on chromosome 17p. J Med Genet. 1998 Sep;35(9):770–772. doi: 10.1136/jmg.35.9.770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Jacobson S. G., Cideciyan A. V., Regunath G., Rodriguez F. J., Vandenburgh K., Sheffield V. C., Stone E. M. Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. Nat Genet. 1995 Sep;11(1):27–32. doi: 10.1038/ng0995-27. [DOI] [PubMed] [Google Scholar]
  43. Jacobson Samuel G., Cideciyan Artur V., Bennett Jean, Kingsley Ronald M., Sheffield Val C., Stone Edwin M. Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Arch Ophthalmol. 2002 Mar;120(3):376–379. doi: 10.1001/archopht.120.3.376. [DOI] [PubMed] [Google Scholar]
  44. Kajiwara K., Hahn L. B., Mukai S., Travis G. H., Berson E. L., Dryja T. P. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature. 1991 Dec 12;354(6353):480–483. doi: 10.1038/354480a0. [DOI] [PubMed] [Google Scholar]
  45. Kaplan J., Gerber S., Larget-Piet D., Rozet J. M., Dollfus H., Dufier J. L., Odent S., Postel-Vinay A., Janin N., Briard M. L. A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1. Nat Genet. 1993 Nov;5(3):308–311. doi: 10.1038/ng1193-308. [DOI] [PubMed] [Google Scholar]
  46. Kelsell R. E., Godley B. F., Evans K., Tiffin P. A., Gregory C. Y., Plant C., Moore A. T., Bird A. C., Hunt D. M. Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q. Hum Mol Genet. 1995 Sep;4(9):1653–1656. doi: 10.1093/hmg/4.9.1653. [DOI] [PubMed] [Google Scholar]
  47. Kemp C. M., Jacobson S. G., Cideciyan A. V., Kimura A. E., Sheffield V. C., Stone E. M. RDS gene mutations causing retinitis pigmentosa or macular degeneration lead to the same abnormality in photoreceptor function. Invest Ophthalmol Vis Sci. 1994 Jul;35(8):3154–3162. [PubMed] [Google Scholar]
  48. Klaver C. C., Kliffen M., van Duijn C. M., Hofman A., Cruts M., Grobbee D. E., van Broeckhoven C., de Jong P. T. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet. 1998 Jul;63(1):200–206. doi: 10.1086/301901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Klaver C. C., Wolfs R. C., Assink J. J., van Duijn C. M., Hofman A., de Jong P. T. Genetic risk of age-related maculopathy. Population-based familial aggregation study. Arch Ophthalmol. 1998 Dec;116(12):1646–1651. doi: 10.1001/archopht.116.12.1646. [DOI] [PubMed] [Google Scholar]
  50. Klein M. L., Schultz D. W., Edwards A., Matise T. C., Rust K., Berselli C. B., Trzupek K., Weleber R. G., Ott J., Wirtz M. K. Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. Arch Ophthalmol. 1998 Aug;116(8):1082–1088. doi: 10.1001/archopht.116.8.1082. [DOI] [PubMed] [Google Scholar]
  51. Kniazeva M., Chiang M. F., Morgan B., Anduze A. L., Zack D. J., Han M., Zhang K. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4. Am J Hum Genet. 1999 May;64(5):1394–1399. doi: 10.1086/302377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Kniazeva M., Traboulsi E. I., Yu Z., Stefko S. T., Gorin M. B., Shugart Y. Y., O'Connell J. R., Blaschak C. J., Cutting G., Han M. A new locus for dominant drusen and macular degeneration maps to chromosome 6q14. Am J Ophthalmol. 2000 Aug;130(2):197–202. doi: 10.1016/s0002-9394(00)00585-7. [DOI] [PubMed] [Google Scholar]
  53. Kremer H., Pinckers A., van den Helm B., Deutman A. F., Ropers H. H., Mariman E. C. Localization of the gene for dominant cystoid macular dystrophy on chromosome 7p. Hum Mol Genet. 1994 Feb;3(2):299–302. doi: 10.1093/hmg/3.2.299. [DOI] [PubMed] [Google Scholar]
  54. Lois N., Holder G. E., Bunce C., Fitzke F. W., Bird A. C. Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol. 2001 Mar;119(3):359–369. doi: 10.1001/archopht.119.3.359. [DOI] [PubMed] [Google Scholar]
  55. Lois N., Holder G. E., Fitzke F. W., Plant C., Bird A. C. Intrafamilial variation of phenotype in Stargardt macular dystrophy-Fundus flavimaculatus. Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2668–2675. [PubMed] [Google Scholar]
  56. Lotery A. J., Ennis K. T., Silvestri G., Nicholl S., McGibbon D., Collins A. D., Hughes A. E. Localisation of a gene for central areolar choroidal dystrophy to chromosome 17p. Hum Mol Genet. 1996 May;5(5):705–708. doi: 10.1093/hmg/5.5.705. [DOI] [PubMed] [Google Scholar]
  57. Lotery A. J., Munier F. L., Fishman G. A., Weleber R. G., Jacobson S. G., Affatigato L. M., Nichols B. E., Schorderet D. F., Sheffield V. C., Stone E. M. Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000 May;41(6):1291–1296. [PubMed] [Google Scholar]
  58. Majid Mohammed A., Smith Valerie A., Easty David L., Baker Andrew H., Newby Andrew C. Sorsby's fundus dystrophy mutant tissue inhibitors of metalloproteinase-3 induce apoptosis of retinal pigment epithelial and MCF-7 cells. FEBS Lett. 2002 Oct 9;529(2-3):281–285. doi: 10.1016/s0014-5793(02)03359-8. [DOI] [PubMed] [Google Scholar]
  59. Manschot W. A. Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol. 1972 Aug;88(2):131–138. doi: 10.1001/archopht.1972.01000030133002. [DOI] [PubMed] [Google Scholar]
  60. Marmorstein A. D., Marmorstein L. Y., Rayborn M., Wang X., Hollyfield J. G., Petrukhin K. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12758–12763. doi: 10.1073/pnas.220402097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Marmorstein Lihua Y., Munier Francis L., Arsenijevic Yvan, Schorderet Daniel F., McLaughlin Precious J., Chung Daniel, Traboulsi Elias, Marmorstein Alan D. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002 Sep 19;99(20):13067–13072. doi: 10.1073/pnas.202491599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Martínez-Mir A., Bayés M., Vilageliu L., Grinberg D., Ayuso C., del Río T., García-Sandoval B., Bussaglia E., Baiget M., Gonzàlez-Duarte R. A new locus for autosomal recessive retinitis pigmentosa (RP19) maps to 1p13-1p21. Genomics. 1997 Feb 15;40(1):142–146. doi: 10.1006/geno.1996.4528. [DOI] [PubMed] [Google Scholar]
  63. Martínez-Mir A., Paloma E., Allikmets R., Ayuso C., del Rio T., Dean M., Vilageliu L., Gonzàlez-Duarte R., Balcells S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet. 1998 Jan;18(1):11–12. doi: 10.1038/ng0198-11. [DOI] [PubMed] [Google Scholar]
  64. Massin P., Guillausseau P. J., Vialettes B., Paquis V., Orsini F., Grimaldi A. D., Gaudric A. Macular pattern dystrophy associated with a mutation of mitochondrial DNA. Am J Ophthalmol. 1995 Aug;120(2):247–248. doi: 10.1016/s0002-9394(14)72615-7. [DOI] [PubMed] [Google Scholar]
  65. Massin P., Virally-Monod M., Vialettes B., Paques M., Gin H., Porokhov B., Caillat-Zucman S., Froguel P., Paquis-Fluckinger V., Gaudric A. Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group. Ophthalmology. 1999 Sep;106(9):1821–1827. doi: 10.1016/s0161-6420(99)90356-1. [DOI] [PubMed] [Google Scholar]
  66. Mata N. L., Tzekov R. T., Liu X., Weng J., Birch D. G., Travis G. H. Delayed dark-adaptation and lipofuscin accumulation in abcr+/- mice: implications for involvement of ABCR in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001 Jul;42(8):1685–1690. [PubMed] [Google Scholar]
  67. Mata N. L., Weng J., Travis G. H. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7154–7159. doi: 10.1073/pnas.130110497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Maugeri A., Klevering B. J., Rohrschneider K., Blankenagel A., Brunner H. G., Deutman A. F., Hoyng C. B., Cremers F. P. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet. 2000 Aug 24;67(4):960–966. doi: 10.1086/303079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Maugeri A., van Driel M. A., van de Pol D. J., Klevering B. J., van Haren F. J., Tijmes N., Bergen A. A., Rohrschneider K., Blankenagel A., Pinckers A. J. 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. 1999 Apr;64(4):1024–1035. doi: 10.1086/302323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Maw M. A., Corbeil D., Koch J., Hellwig A., Wilson-Wheeler J. C., Bridges R. J., Kumaramanickavel G., John S., Nancarrow D., Röper K. A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet. 2000 Jan 1;9(1):27–34. doi: 10.1093/hmg/9.1.27. [DOI] [PubMed] [Google Scholar]
  71. Meyers S. M., Zachary A. A. Monozygotic twins with age-related macular degeneration. Arch Ophthalmol. 1988 May;106(5):651–653. doi: 10.1001/archopht.1988.01060130705029. [DOI] [PubMed] [Google Scholar]
  72. Michaelides Michel, Johnson Samantha, Poulson Arabella, Bradshaw Keith, Bellmann Caren, Hunt David M., Moore Anthony T. An autosomal dominant bull's-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4. Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1657–1662. doi: 10.1167/iovs.02-0941. [DOI] [PubMed] [Google Scholar]
  73. Michaelides Michel, Johnson Samantha, Tekriwal Alok K., Holder Graham E., Bellmann Caren, Kinning Esther, Woodruff Geoffrey, Trembath Richard C., Hunt David M., Moore Anthony T. An early-onset autosomal dominant macular dystrophy (MCDR3) resembling North Carolina macular dystrophy maps to chromosome 5. Invest Ophthalmol Vis Sci. 2003 May;44(5):2178–2183. doi: 10.1167/iovs.02-1094. [DOI] [PubMed] [Google Scholar]
  74. Mohler C. W., Fine S. L. Long-term evaluation of patients with Best's vitelliform dystrophy. Ophthalmology. 1981 Jul;88(7):688–692. doi: 10.1016/s0161-6420(81)34965-3. [DOI] [PubMed] [Google Scholar]
  75. Molday L. L., Hicks D., Sauer C. G., Weber B. H., Molday R. S. Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells. Invest Ophthalmol Vis Sci. 2001 Mar;42(3):816–825. [PubMed] [Google Scholar]
  76. Molday L. L., Rabin A. R., Molday R. S. ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy. Nat Genet. 2000 Jul;25(3):257–258. doi: 10.1038/77004. [DOI] [PubMed] [Google Scholar]
  77. Nichols B. E., Drack A. V., Vandenburgh K., Kimura A. E., Sheffield V. C., Stone E. M. A 2 base pair deletion in the RDS gene associated with butterfly-shaped pigment dystrophy of the fovea. Hum Mol Genet. 1993 May;2(5):601–603. doi: 10.1093/hmg/2.5.601. [DOI] [PubMed] [Google Scholar]
  78. Nichols B. E., Sheffield V. C., Vandenburgh K., Drack A. V., Kimura A. E., Stone E. M. Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nat Genet. 1993 Mar;3(3):202–207. doi: 10.1038/ng0393-202. [DOI] [PubMed] [Google Scholar]
  79. Paloma Eva, Coco Rosa, Martínez-Mir Amalia, Vilageliu Lluïsa, Balcells Susana, Gonzàlez-Duarte Roser. Analysis of ABCA4 in mixed Spanish families segregating different retinal dystrophies. Hum Mutat. 2002 Dec;20(6):476–476. doi: 10.1002/humu.9086. [DOI] [PubMed] [Google Scholar]
  80. Petrukhin K., Koisti M. J., Bakall B., Li W., Xie G., Marknell T., Sandgren O., Forsman K., Holmgren G., Andreasson S. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998 Jul;19(3):241–247. doi: 10.1038/915. [DOI] [PubMed] [Google Scholar]
  81. Pianta Michael J., Aleman Tomas S., Cideciyan Artur V., Sunness Janet S., Li Yuanyuan, Campochiaro Betsy A., Campochiaro Peter A., Zack Donald J., Stone Edwin M., Jacobson Samuel G. In vivo micropathology of Best macular dystrophy with optical coherence tomography. Exp Eye Res. 2003 Feb;76(2):203–211. doi: 10.1016/s0014-4835(02)00280-4. [DOI] [PubMed] [Google Scholar]
  82. Poetsch A., Molday L. L., Molday R. S. The cGMP-gated channel and related glutamic acid-rich proteins interact with peripherin-2 at the rim region of rod photoreceptor disc membranes. J Biol Chem. 2001 Oct 18;276(51):48009–48016. doi: 10.1074/jbc.M108941200. [DOI] [PubMed] [Google Scholar]
  83. Qi Jian Hua, Ebrahem Quteba, Moore Nina, Murphy Gillian, Claesson-Welsh Lena, Bond Mark, Baker Andrew, Anand-Apte Bela. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med. 2003 Mar 24;9(4):407–415. doi: 10.1038/nm846. [DOI] [PubMed] [Google Scholar]
  84. Rabb M. F., Mullen L., Yelchits S., Udar N., Small K. W. A North Carolina macular dystrophy phenotype in a Belizean family maps to the MCDR1 locus. Am J Ophthalmol. 1998 Apr;125(4):502–508. doi: 10.1016/s0002-9394(99)80191-3. [DOI] [PubMed] [Google Scholar]
  85. Radu Roxana A., Mata Nathan L., Nusinowitz Steven, Liu Xinran, Sieving Paul A., Travis Gabriel H. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A. 2003 Apr 1;100(8):4742–4747. doi: 10.1073/pnas.0737855100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Reardon W., Ross R. J., Sweeney M. G., Luxon L. M., Pembrey M. E., Harding A. E., Trembath R. C. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet. 1992 Dec 5;340(8832):1376–1379. doi: 10.1016/0140-6736(92)92560-3. [DOI] [PubMed] [Google Scholar]
  87. Reichel M. B., Kelsell R. E., Fan J., Gregory C. Y., Evans K., Moore A. T., Hunt D. M., Fitzke F. W., Bird A. C. Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q. Br J Ophthalmol. 1998 Oct;82(10):1162–1168. doi: 10.1136/bjo.82.10.1162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Rivera A., White K., Stöhr H., Steiner K., Hemmrich N., Grimm T., Jurklies B., Lorenz B., Scholl H. P., Apfelstedt-Sylla E. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Aug 24;67(4):800–813. doi: 10.1086/303090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Rozet J. M., Gerber S., Souied E., Perrault I., Châtelin S., Ghazi I., Leowski C., Dufier J. L., Munnich A., Kaplan J. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies. Eur J Hum Genet. 1998 May-Jun;6(3):291–295. doi: 10.1038/sj.ejhg.5200221. [DOI] [PubMed] [Google Scholar]
  90. Sarra G. M., Stephens C., de Alwis M., Bainbridge J. W., Smith A. J., Thrasher A. J., Ali R. R. Gene replacement therapy in the retinal degeneration slow (rds) mouse: the effect on retinal degeneration following partial transduction of the retina. Hum Mol Genet. 2001 Oct 1;10(21):2353–2361. doi: 10.1093/hmg/10.21.2353. [DOI] [PubMed] [Google Scholar]
  91. Sauer C. G., Gehrig A., Warneke-Wittstock R., Marquardt A., Ewing C. C., Gibson A., Lorenz B., Jurklies B., Weber B. H. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet. 1997 Oct;17(2):164–170. doi: 10.1038/ng1097-164. [DOI] [PubMed] [Google Scholar]
  92. Simonelli F., Testa F., de Crecchio G., Rinaldi E., Hutchinson A., Atkinson A., Dean M., D'Urso M., Allikmets R. New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2000 Mar;41(3):892–897. [PubMed] [Google Scholar]
  93. Small K. W. North Carolina macular dystrophy: clinical features, genealogy, and genetic linkage analysis. Trans Am Ophthalmol Soc. 1998;96:925–961. [PMC free article] [PubMed] [Google Scholar]
  94. Small K. W., Udar N., Yelchits S., Klein R., Garcia C., Gallardo G., Puech B., Puech V., Saperstein D., Lim J. North Carolina macular dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis. Mol Vis. 1999 Dec 29;5:38–38. [PubMed] [Google Scholar]
  95. Sparrow J. R., Nakanishi K., Parish C. A. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 2000 Jun;41(7):1981–1989. [PubMed] [Google Scholar]
  96. Sparrow Janet R., Zhou Jilin, Ben-Shabat Shimon, Vollmer Heidi, Itagaki Yasuhiro, Nakanishi Koji. Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci. 2002 Apr;43(4):1222–1227. [PubMed] [Google Scholar]
  97. Stefko S. T., Zhang K., Gorin M. B., Traboulsi E. I. Clinical spectrum of chromosome 6-linked autosomal dominant drusen and macular degeneration. Am J Ophthalmol. 2000 Aug;130(2):203–208. doi: 10.1016/s0002-9394(00)00562-6. [DOI] [PubMed] [Google Scholar]
  98. Steinmetz R. L., Haimovici R., Jubb C., Fitzke F. W., Bird A. C. Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change. Br J Ophthalmol. 1993 Sep;77(9):549–554. doi: 10.1136/bjo.77.9.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Stone E. M., Lotery A. J., Munier F. L., Héon E., Piguet B., Guymer R. H., Vandenburgh K., Cousin P., Nishimura D., Swiderski R. E. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999 Jun;22(2):199–202. doi: 10.1038/9722. [DOI] [PubMed] [Google Scholar]
  100. Stone E. M., Nichols B. E., Kimura A. E., Weingeist T. A., Drack A., Sheffield V. C. Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q. Arch Ophthalmol. 1994 Jun;112(6):765–772. doi: 10.1001/archopht.1994.01090180063036. [DOI] [PubMed] [Google Scholar]
  101. Stone E. M., Sheffield V. C., Hageman G. S. Molecular genetics of age-related macular degeneration. Hum Mol Genet. 2001 Oct 1;10(20):2285–2292. doi: 10.1093/hmg/10.20.2285. [DOI] [PubMed] [Google Scholar]
  102. Stone E. M., Webster A. R., Vandenburgh K., Streb L. M., Hockey R. R., Lotery A. J., Sheffield V. C. Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration. Nat Genet. 1998 Dec;20(4):328–329. doi: 10.1038/3798. [DOI] [PubMed] [Google Scholar]
  103. Sun H., Molday R. S., Nathans J. Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J Biol Chem. 1999 Mar 19;274(12):8269–8281. doi: 10.1074/jbc.274.12.8269. [DOI] [PubMed] [Google Scholar]
  104. Sun H., Nathans J. Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments. Nat Genet. 1997 Sep;17(1):15–16. doi: 10.1038/ng0997-15. [DOI] [PubMed] [Google Scholar]
  105. Sun H., Smallwood P. M., Nathans J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000 Oct;26(2):242–246. doi: 10.1038/79994. [DOI] [PubMed] [Google Scholar]
  106. Sun Hui, Tsunenari Takashi, Yau King-Wai, Nathans Jeremy. The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4008–4013. doi: 10.1073/pnas.052692999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Swann P. G., Lovie-Kitchin J. E. Age-related maculopathy. I: A review of its morphology and effects on visual function. Ophthalmic Physiol Opt. 1990 Apr;10(2):149–158. doi: 10.1111/j.1475-1313.1990.tb00969.x. [DOI] [PubMed] [Google Scholar]
  108. Tarttelin E. E., Gregory-Evans C. Y., Bird A. C., Weleber R. G., Klein M. L., Blackburn J., Gregory-Evans K. Molecular genetic heterogeneity in autosomal dominant drusen. J Med Genet. 2001 Jun;38(6):381–384. doi: 10.1136/jmg.38.6.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Travis G. H., Sutcliffe J. G., Bok D. The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein. Neuron. 1991 Jan;6(1):61–70. doi: 10.1016/0896-6273(91)90122-g. [DOI] [PubMed] [Google Scholar]
  110. Weber B. H., Vogt G., Pruett R. C., Stöhr H., Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet. 1994 Dec;8(4):352–356. doi: 10.1038/ng1294-352. [DOI] [PubMed] [Google Scholar]
  111. Weber B. H., Walker D., Müller B. Molecular evidence for non-penetrance in Best's disease. J Med Genet. 1994 May;31(5):388–392. doi: 10.1136/jmg.31.5.388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Weber Bernhard H. F., Lin Biaoyang, White Karen, Kohler Konrad, Soboleva Galina, Herterich Sabine, Seeliger Mathias W., Jaissle Gesine B., Grimm Christian, Reme Charlotte. A mouse model for Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci. 2002 Aug;43(8):2732–2740. [PubMed] [Google Scholar]
  113. Weber Bernhard H. F., Schrewe Heinrich, Molday Laurie L., Gehrig Andrea, White Karen L., Seeliger Mathias W., Jaissle Gesine B., Friedburg Christoph, Tamm Ernst, Molday Robert S. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6222–6227. doi: 10.1073/pnas.092528599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Webster A. R., Héon E., Lotery A. J., Vandenburgh K., Casavant T. L., Oh K. T., Beck G., Fishman G. A., Lam B. L., Levin A. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179–1189. [PubMed] [Google Scholar]
  115. Weeks D. E., Conley Y. P., Mah T. S., Paul T. O., Morse L., Ngo-Chang J., Dailey J. P., Ferrell R. E., Gorin M. B. A full genome scan for age-related maculopathy. Hum Mol Genet. 2000 May 22;9(9):1329–1349. doi: 10.1093/hmg/9.9.1329. [DOI] [PubMed] [Google Scholar]
  116. Weeks D. E., Conley Y. P., Tsai H. J., Mah T. S., Rosenfeld P. J., Paul T. O., Eller A. W., Morse L. S., Dailey J. P., Ferrell R. E. Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol. 2001 Nov;132(5):682–692. doi: 10.1016/s0002-9394(01)01214-4. [DOI] [PubMed] [Google Scholar]
  117. Weingeist T. A., Kobrin J. L., Watzke R. C. Histopathology of Best's macular dystrophy. Arch Ophthalmol. 1982 Jul;100(7):1108–1114. doi: 10.1001/archopht.1982.01030040086016. [DOI] [PubMed] [Google Scholar]
  118. Weleber R. G., Carr R. E., Murphey W. H., Sheffield V. C., Stone E. M. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol. 1993 Nov;111(11):1531–1542. doi: 10.1001/archopht.1993.01090110097033. [DOI] [PubMed] [Google Scholar]
  119. Weng J., Mata N. L., Azarian S. M., Tzekov R. T., Birch D. G., Travis G. H. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell. 1999 Jul 9;98(1):13–23. doi: 10.1016/S0092-8674(00)80602-9. [DOI] [PubMed] [Google Scholar]
  120. Yanoff M., Kertesz Rahn E., Zimmerman L. E. Histopathology of juvenile retinoschisis. Arch Ophthalmol. 1968 Jan;79(1):49–53. doi: 10.1001/archopht.1968.03850040051014. [DOI] [PubMed] [Google Scholar]
  121. Young R. W. Pathophysiology of age-related macular degeneration. Surv Ophthalmol. 1987 Mar-Apr;31(5):291–306. doi: 10.1016/0039-6257(87)90115-9. [DOI] [PubMed] [Google Scholar]
  122. Zhang K., Kniazeva M., Han M., Li W., Yu Z., Yang Z., Li Y., Metzker M. L., Allikmets R., Zack D. J. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet. 2001 Jan;27(1):89–93. doi: 10.1038/83817. [DOI] [PubMed] [Google Scholar]
  123. van Driel M. A., Maugeri A., Klevering B. J., Hoyng C. B., Cremers F. P. ABCR unites what ophthalmologists divide(s) Ophthalmic Genet. 1998 Sep;19(3):117–122. doi: 10.1076/opge.19.3.117.2187. [DOI] [PubMed] [Google Scholar]
  124. van den Ouweland J. M., Lemkes H. H., Ruitenbeek W., Sandkuijl L. A., de Vijlder M. F., Struyvenberg P. A., van de Kamp J. J., Maassen J. A. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368–371. doi: 10.1038/ng0892-368. [DOI] [PubMed] [Google Scholar]
  125. von Rückmann A., Fitzke F. W., Bird A. C. Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 1995 May;79(5):407–412. doi: 10.1136/bjo.79.5.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. von Rückmann A., Fitzke F. W., Bird A. C. Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope. Invest Ophthalmol Vis Sci. 1997 Feb;38(2):478–486. [PubMed] [Google Scholar]
  127. von Rückmann A., Fitzke F. W., Bird A. C. In vivo fundus autofluorescence in macular dystrophies. Arch Ophthalmol. 1997 May;115(5):609–615. doi: 10.1001/archopht.1997.01100150611006. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES