The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe

Article metrics


Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3


  1. 1

    Allikmets R, Singh N, Sun H et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy Nat Genet 1997 15: 236–246

  2. 2

    Rozet J-M, Gerber S, Souied E et al. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies Eur J Hum Genet 1998 6: 291–295

  3. 3

    Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR . Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene Arch Ophthalmol 1999 117: 504–510

  4. 4

    Lewis RA, Shroyer NF, Singh N et al. Genotype/phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease Am J Hum Genet 1999 64: 422–434

  5. 5

    Maugeri A, van Driel MA, van de Pol TJR et al. 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 64: 1024–1035

  6. 6

    Papaioannou M, Ocaka L, Bessant D et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies Invest Ophthalmol Vis Sci 2000 41: 16–19

  7. 7

    Rivera A, White K, Stohr H et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration Am J Hum Genet 2000 67: 800–813

  8. 8

    Simonelli F, Testa F, de Crecchio G et al. New ABCR mutations and clinical phenotype in Italian patients with Stargardt disease Invest Ophthalmol Vis Sci 2000 41: 892–897

  9. 9

    Webster AR, Heon E, Lotery AJ et al. An analysis of allelic variation in the ABCA4 gene Invest Ophthalmol Vis Sci 2001 42: 1179–1189

  10. 10

    Paloma E, Martinez-Mir A, Vilageliu L, Gonzalez-Duarte R, Balcells S . Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies Hum Mutat 2001 17: 504–510

  11. 11

    Cremers FPM, van de Pol TJR, van Driel M et al. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR Hum Mol Genet 1998 7: 355–362

  12. 12

    Maugeri A, Klevering BJ, Rohrschneider K et al. Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy Am J Hum Genet 2000 67: 960–966

  13. 13

    Martinez-Mir A, Paloma E, Allikmets R et al. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR Nat Genet 1998 18: 11–12

  14. 14

    Rozet J-M, Gerber S, Ghazi I et al. Mutations of the retinal specific ATP binding transporter gene (ABCR) in a single family segregating both autosomal recessive retinitis pigmentosa RP19 and Stargardt disease: evidence of clinical heterogeneity at this locus J Med Genet 1999 36: 447–451

  15. 15

    Allikmets R, Shroyer NF, Singh N et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration Science 1997 277: 1805–1807

  16. 16

    Allikmets R, . the International ABCR Screening Consortium Further evidence for an association of ABCR alleles with age-related macular degeneration Am J Hum Genet 2000 67: 487–491

  17. 17

    Allikmets R . Simple and complex ABCR: genetic predisposition to retinal disease Am J Hum Genet 2000 67: 793–799

  18. 18

    Rozet JM, Gerber S, Perrault I et al. A single gene accounts for at least three different conditions: the Stargardt's paradox Am J Hum Genet 1997 61: A105

  19. 19

    van Driel MA, Maugeri A, Klevering BJ, Hoyng CB, Cremers FPM . ABCR unites what ophthalmologists divide(s) Ophthalmic Genet 1998 19: 117–122

  20. 20

    Molday LL, Rabin AR, Molday RS . ABCR expression in foveal cone photoreceptors and its role in stargardt macular dystrophy Nat Genet 2000 25: 257–258

  21. 21

    Sun H, Molday RS, 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 274: 8269–8281

  22. 22

    Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH . Insights into the function of rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice Cell 1999 98: 13–23

  23. 23

    Sun H, Smallwood PM, Nathans J . Biochemical defects in ABCR protein variants associated with human retinopathies Nat Genet 2000 26: 242–246

  24. 24

    Shuber AP, Skoletsky J, Stern R, Handelin BL . Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis Hum Mol Genet 1993 2: 153–158

  25. 25

    Newton CR, Graham A, Heptinstall LE et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS) Nucleic Acids Res 1989 17: 2503–2516

  26. 26

    Risch N, de Leon D, Ozelius L et al. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population Nat Genet 1995 9: 152–159

  27. 27

    Gasparini P, Rabionet R, Barbujani G et al. High carrier frequency of the 35delG deafness mutation in European populations Eur J Hum Genet 2000 8: 19–23

  28. 28

    Lucotte G, Hazout S, De Braekeleer M . Complete map of cystic fibrosis mutation DF508 frequencies in Western Europe and correlation between mutation frequencies and incidence of disease Hum Biol 1995 67: 797–803

  29. 29

    Lucotte G, Hazout S . Geographic and ethnic distributions of the more frequent cystic fibrosis mutations in Europe show that a founder effect is apparent for several mutant alleles Hum Biol 1995 67: 561–576

  30. 30

    Peelen T, van Vliet M, Petrij-Bosch A et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families Am J Hum Genet 1997 60: 1041–1049

  31. 31

    Libert F, Cochaux P, Beckman G et al. The deltaCCR5 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe Hum Mol Genet 1998 7: 399–406

  32. 32

    Van Laer L, Coucke P, Mueller RF et al. A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment J Med Genet 2001 38: 515–518

  33. 33

    Pier GB, Grout M, Zaidi T et al. Salmonella Typhi uses CFTR to enter intestinal epithelial cells Nature 1998 393: 79–82

  34. 34

    den Hollander AI, van Driel MA, de Kok YJM et al. Isolation and mapping of novel candidate genes for retinal disorders using suppression subtractive hybridization Genomics 1999 58: 240–249

  35. 35

    Konrad PN, Richards F, Valentine WN, Paglia DE . Gamma-glutamyl-cysteine synthetase deficiency: a cause of hereditary hemolitic anemia New Engl J Med 1972 286: 557–561

  36. 36

    Blacharski PA . Fundus flavimaculatus in Newsome DA (ed): Retinal dystrophies and degenerations Raven Press, New York 1988 pp 135–159

Download references


The authors thank SD van der Velde-Visser for expert technical assistance and D Gallardo who kindly supplied anonymous blood samples. This work was supported by the British Retinitis Pigmentosa Society, the ProRetina Deutschland, the Deutsche Forschungsgemeinschaft (We 1259/10-1), the NIH (EY13435), the Research to Prevent Blindness, the Steinbach Fund (R Allikmets), the Spanish Ministerio de Ciencia y Tecnología (PM99-0168), the Fundaluce (04-2001), the Regione Campania (L.R. 41/98 and L.R. 41/99), the Swedish Medical Research Council (09747), The Association Retina France and The Foundation Paulette Darty.

Author information

Correspondence to Alessandra Maugeri.

Rights and permissions

Reprints and Permissions

About this article


  • ABCA4
  • ABCR
  • carrier frequency
  • founder mutation
  • STGD
  • retinal dystrophies

Further reading