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1 From the Program in Cell and Molecular Biology 2 Departments of Molecular and Human Genetics, 4 Pediatrics, 5 Medicine, and 6 Ophthalmology, Baylor College of Medicine, Houston, Texas.
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.
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