Human Genetics

, Volume 108, Issue 4, pp 346–355

Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4)

  • Alexander Yatsenko
  • Noah Shroyer
  • Richard Lewis
  • James Lupski
Original Investigation

DOI: 10.1007/s004390100493

Cite this article as:
Yatsenko, A., Shroyer, N., Lewis, R. et al. Hum Genet (2001) 108: 346. doi:10.1007/s004390100493
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Abstract.

Based on recent studies of the photoreceptor-specific ABC transporter gene ABCR (ABCA4) in Stargardt disease (STGD1) and other retinal dystrophies, we and others have developed a model in which the severity of retinal disease correlates inversely with residual ABCR activity. This model predicts that patients with late-onset STGD1 may retain partial ABCR activity attributable to mild missense alleles. To test this hypothesis, we used late-onset STGD1 patients (onset: ≥35 years) to provide an in vivo functional analysis of various combinations of mutant alleles. We sequenced directly the entire coding region of ABCR and detected mutations in 33/50 (66%) disease chromosomes, but surprisingly, 11/33 (33%) were truncating alleles. Importantly, all 22 missense mutations were located outside the known functional domains of ABCR (ATP-binding or transmembrane), whereas in our general cohort of STGD1 subjects, alterations occurred with equal frequency across the entire protein. We suggest that these missense mutations in regions of unknown function are milder alleles and more susceptible to modifier effects. Thus, we have corroborated a prediction from the model of ABCR pathogenicity that (1) one mutant ABCR allele is always missense in late-onset STGD1 patients, and (2) the age-of-onset is correlated with the amount of ABCR activity of this allele. In addition, we report three new pseudodominant families that now comprise eight of 178 outbred STGD1 families and suggest a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (~1/22).

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Alexander Yatsenko
    • 1
  • Noah Shroyer
    • 1
  • Richard Lewis
    • 1
  • James Lupski
    • 1
  1. 1.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  2. 2.Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
  3. 3.Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  4. 4.Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
  5. 5.Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA
  6. 6.Present address: Baylor College of Medicine, 604B, One Baylor Plaza, Houston, TX 77030, USA, e-mail: jlupski@bcm.tmc.edu, Tel.: +1-713-7986530, Fax: +1-713-7985073