Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa

Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2757-61.


Purpose: To determine the type of ABCR mutations that segregate in a family that manifests both Stargardt disease (STGD) and retinitis pigmentosa (RP), and the functional consequences of the underlying mutations.

Methods: Direct sequencing of all 50 exons and flanking intronic regions of ABCR was performed for the STGD- and RP-affected relatives. RNA hybridization, Western blot analysis, and azido-adenosine triphosphate (ATP) labeling was used to determine the effect of disease-associated ABCR mutations in an in vitro assay system.

Results: Compound heterozygous missense mutations were identified in patients with STGD and RP. STGD-affected individual AR682-03 was compound heterozygous for the mutation 2588G-->C and a complex allele, [W1408R; R1640W]. RP-affected individuals AR682-04 and-05 were compound heterozygous for the complex allele [W1408R; R1640W] and the missense mutation V767D. Functional analysis of the mutation V767D by Western blot and ATP binding revealed a severe reduction in protein expression. In vitro analysis of ABCR protein with the mutations W1408R and R1640W showed a moderate effect of these individual mutations on expression and ATP-binding; the complex allele [W1408R; R1640W] caused a severe reduction in protein expression.

Conclusions: These data reveal that missense ABCR mutations may be associated with RP. Functional analysis reveals that the RP-associated missense ABCR mutations are likely to be functionally null. These studies of the complex allele W1408R; R1640W suggest a synergistic effect of the individual mutations. These data are congruent with a model in which RP is associated with homozygous null mutations and with the notion that severity of retinal disease is inversely related to residual ABCR activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Adenosine Triphosphate / metabolism
  • Adolescent
  • Aged
  • Blotting, Western
  • DNA Mutational Analysis
  • Female
  • Fundus Oculi
  • Humans
  • Macular Degeneration / complications
  • Macular Degeneration / diagnosis
  • Macular Degeneration / genetics*
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Retinitis Pigmentosa / complications
  • Retinitis Pigmentosa / diagnosis
  • Retinitis Pigmentosa / genetics*
  • Sequence Analysis, DNA


  • ABCA4 protein, human
  • ATP-Binding Cassette Transporters
  • Adenosine Triphosphate