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A new dominant RPE65-associated inherited retinal disease (IRD) caused by the p.(E519K) founder variant was discovered. This finding identifies a novel therapeutic target for dominant IRD.

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Area of Science:

  • Genetics
  • Ophthalmology
  • Molecular Biology

Background:

  • Recessive RPE65-associated retinopathy is a known target for gene therapy.
  • Dominant RPE65-associated retinopathy is rare, with only one previous report of the Irish founder variant p.(D477G).

Purpose of the Study:

  • To report the discovery of a novel, second dominant RPE65-associated retinopathy.
  • To identify the causative genetic variant, p.(E519K), and characterize its effects.

Main Methods:

  • Genomic data analysis in discovery (n=2873) and replication (n=18,796) cohorts with inherited retinal disease (IRD).
  • Extensive phenotyping of heterozygous p.(E519K) individuals.
  • In vitro functional assays (enzymatic assay, Western blotting, co-immunoprecipitation, CETSA, minigene assays) and in silico protein modeling (AlphaFold).

Main Results:

  • The monoallelic p.(E519K) variant was identified in 83 affected individuals from multiple European countries, indicating a founder effect.
  • Variant p.(E519K) was shown to decrease RPE65 protein expression and enzymatic activity, with altered protein stability.
  • Genotype-phenotype correlation revealed dominant inheritance and phenotypic variability, characterized by late-onset macular dystrophy with two subtypes.

Conclusions:

  • The discovery of dominant RPE65-IRD due to the p.(E519K) founder variant expands the known genetic causes of dominant IRD.
  • This finding reduces the diagnostic gap for dominant IRD and presents a new therapeutic target.