A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber congenital amaurosis

Eduardo Silva, Sharola Dharmaraj, Ying Ying Li, Ana Luisa Pina, Robert Colin Carter, Magali Loyer, Elias Traboulsi, George Theodossiadis, Robert K. Koenekoop, Olof H. Sundin, Irene H. Maumenee

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19 Scopus citations


Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous severe retinal dystrophy presenting in infancy. To explain the phenotypical variability observed in two affected siblings of a consanguineous pedigree diagnosed with LCA and establish a genotype-phenotype correlation, we screened GUCY2D, RPE65, CRX, AIPL1, and RPGRIP1 for mutations. The more severely affected sibling carried a heterozygous missense mutation in the GUCY2D gene (Ile539Val), which did not segregate with the disease phenotype. Subsequently, a homozygous nonsense mutation (Glu102STOP) in the RPE65 gene was identified in both affected siblings, thus identifying the causative gene. This data provides evidence for the presence of genetic modulation in LCA. It appears that the heterozygous GUCY2D mutation further disrupts the already compromised photoreceptor function resulting in more severe retinal dysfunction in the older sibling. We suggest that the unusual phenotypic variability in these two siblings with LCA is caused by the modifying effect of a heterozygous GUCY2D mutation observed against the disease background of a homozygous RPE65 mutation.

Original languageEnglish (US)
Pages (from-to)205-217
Number of pages13
JournalOphthalmic genetics
Issue number3
StatePublished - Sep 2004


  • GUCY2D
  • Genetic modifier
  • Leber congenital amaurosis
  • RPE65

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Ophthalmology
  • Genetics(clinical)


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