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1 From the Departments of Ophthalmology and Visual Sciences and 2 Biological Chemistry, University of Michigan Medical School, Ann Arbor; the 3 Institute of Human Genetics, University Hospital Hamburg–Eppendorf, Germany; the 4 University Eye Hospital, Department II, Tübingen, Germany; the 5 Department of Pediatric Ophthalmology and Ophthalmogenetics, University of Regensburg, Germany; and 6 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
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 function tests.
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+5ga) have not been reported previously. The most
commonly occurring sequence variant identified in the patients studied
was the IVS1+5ga 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 degeneration.
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