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Br J Ophthalmol 2007;91:1650-1655 doi:10.1136/bjo.2007.118356
  • Extended report
    • Clinical science - Extended reports

ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull’s-eye maculopathy

  1. M Michaelides1,
  2. L L Chen1,
  3. M A Brantley, Jr3,
  4. J L Andorf4,
  5. E M Isaak4,
  6. S A Jenkins2,
  7. G E Holder2,
  8. A C Bird1,
  9. E M Stone4,
  10. A R Webster1
  1. 1
    Institute of Ophthalmology, University College London, London, UK
  2. 2
    Moorfields Eye Hospital, London, UK
  3. 3
    Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
  4. 4
    Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA
  1. Mr A R Webster, Institute of Ophthalmology, University College London, 11–43 Bath Street, London EC1V 9EL, UK; andrew.webster{at}ucl.ac.uk
  • Accepted 29 May 2007

Abstract

Aim: To determine the frequency and nature of mutations in the gene ABCA4 in a cohort of patients with bull’s-eye maculopathy (BEM).

Methods: A panel of 49 subjects (comprising 40 probands/families, 7 sibling pairs and a set of three sibs) with BEM, not attributable to toxic causes, was ascertained. Blood samples from each patient were used to extract genomic DNA, with subsequent mutation screening of the entire coding sequence of ABCA4, using single-strand conformational polymorphism (SSCP) analysis and direct sequencing.

Results: Fourteen probands (35%) were found to have a potentially disease-causing ABCA4 sequence variant on at least one allele. Three patients had a Gly1961Glu missense mutation, the most common variant in Stargardt disease (STGD), with 2 of these subjects having a macular dystrophy (MD) phenotype and a second ABCA4 variant previously associated with STGD. The second most common STGD mutation, Ala1038Val, was seen in one patient with cone–rod dystrophy (CORD). Five novel ABCA4 variants were detected. Two sibships were identified with a similar intra-familial phenotype but discordant ABCA4 variants.

Conclusions: Variations in the ABCA4 gene are common in BEM. Two sibships showed discordant ABCA4 variants. One of these sibships illustrates that ABCA4 variants can be identified in families that have another molecular cause for their disease, due to the high prevalence of ABCA4 disease alleles in the population. The discordance evident in the second sibship may yet also be a chance finding in families with macular disease of another genetic cause, or it may represent a complex mode of inheritance determined/modified by the combination of ABCA4 alleles.

Footnotes

  • Competing interests: None declared.

  • Abbreviations:
    AF

    autofluorescence

    BEM

    bull’s-eye maculopathy

    COD

    cone dystrophy

    CORD

    cone–rod dystrophy

    FFM

    fundus flavimaculatus

    MD

    macular dystrophy

    RCD

    rod–cone dystrophy

    RPE

    retinal pigment epithelium

    SSCP

    single-strand conformational polymorphism

    STGD

    Stargardt disease

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