title: A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber Congenital Amaurosis.
abstract: 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.
authors.affiliation: Molecular and Developmental Biology Laboratory, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Silva
authors.forename: Sharola
authors.initials: S
authors.lastname: Dharmaraj
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Li
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Pina
authors.forename: Robert Colin
authors.initials: RC
authors.lastname: Carter
authors.forename: Magali
authors.initials: M
authors.lastname: Loyer
authors.forename: Elias
authors.initials: E
authors.lastname: Traboulsi
authors.forename: George
authors.initials: G
authors.lastname: Theodossiadis
authors.forename: Robert
authors.initials: R
authors.lastname: Koenekoop
authors.forename: Olof
authors.initials: O
authors.lastname: Sundin
authors.forename: Irene
authors.initials: I
authors.lastname: Maumenee
mesh_terms: D000328:Adult; D001766:Blindness / Q000151:congenital / Q000235:genetics*; D002352:Carrier Proteins; D020090:Chromosome Segregation; D005136:Eye Proteins; D005260:Female; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012162:Retinal Degeneration / Q000151:congenital / Q000235:genetics*; D035781:Siblings; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D006162:Guanylate Cyclase; D011506:Proteins; D011956:Receptors, Cell Surface; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C110715:guanylate cyclase 1