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Debra A. Thompson, Péter Gyürüs, Laura L. Fleischer, Eve L. Bingham, Christina L. McHenry, Eckart Apfelstedt–Sylla, Eberhart Zrenner, Birgit Lorenz, Julia E. Richards, Samuel G. Jacobson, Paul A. Sieving, Andreas Gal; Genetics and Phenotypes of RPE65 Mutations in Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2000;41(13):4293-4299.
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purpose. To characterize the spectrum of RPE65 mutations present
in 453 patients with retinal dystrophy with an interest in
understanding the range of functional deficits attributable to sequence
variants in this gene.
methods. The 14 exons of RPE65 were amplified by polymerase chain
reaction (PCR) from patients’ DNA and analyzed for sequence changes by
single-strand conformation polymorphism (SSCP) and direct sequencing.
Haplotype analysis was performed using RPE65 intragenic
polymorphisms. Patients were examined clinically and with visual
results. Twenty-one different disease-associated DNA sequence changes
predicting missense or nonsense point mutations, insertions, deletions,
and splice site defects in RPE65 were identified in 20
patients in homozygous or compound heterozygous form. In one patient,
paternal uniparental isodisomy (UPD) of chromosome 1 resulted in
homozygosity for a probable functional null allele. Eight of the
disease-associated mutations (Y79H, E95Q, E102X, D167Y, 669delCA,
IVS7+4a→g, G436V, and G528V) and one mutation likely to be associated
with disease (IVS6+5g→a) have not been reported previously. The most
commonly occurring sequence variant identified in the patients studied
was the IVS1+5g→a mutation, accounting for 9 of 40 (22.5%) total
disease alleles. This splice site mutation, as well as R91W, the most
common missense mutation, exists on at least two different genetic
backgrounds. The phenotype resulting from RPE65 mutations appears to be relatively uniform and independent of mutation
class, suggesting that most missense mutations (15 of 40 disease
alleles [37.5%]) result in loss of function. At young ages, this
group of patients has somewhat better subjective visual capacity than
is typically associated with Leber congenital amaurosis (LCA) type I,
with a number of patients retaining some useful visual function beyond
the second decade of life.
conclusions. RPE65 mutations account for a significant percentage
(11.4%) of disease alleles in patients with early-onset retinal
degeneration. The identification and characterization of patients with RPE65 mutations is likely to represent an important
resource for future trials of rational therapies for retinal
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