Mutations inRD3Are Associated with an Extremely Rare and Severe Form of Early Onset Retinal Dystrophy

Abstract

PURPOSE. To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). METHODS.Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/ EOSRD presenting with a BCVA ‡ 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/ EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D.RESULTS. BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3.CONCLUSIONS. This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy. (Invest Ophthalmol Vis Sci.

Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype

“…Indeed, the review of the natural history and clinical data of our patients and that of the two original RD3 families [21], [35] delineate a homogeneous phenotype unambiguously consistent with the diagnosis of congenital and dramatically severe cone-rod dystrophy (LCA type I) originally described in LCA1 patients harboring GUGY2D mutations [3].…”

“…It is tempting to hypothesize that similar to several other LCA genes, mutations with a milder effect on the protein structure and/or function may be responsible for milder phenotypes; for recent reviews see [1], [2]. However, none of the unrelated patients affected by various retinal dystrophies of later-onset and/or severity in our cohort (n = 278) and the other two reported series (n = 907) [21], [35], [40] exhibited disease-causing RD3 mutations. This finding is consistent with the LCA type I-specific involvement of RD3 mutations.…”

“…Significant genotype-phenotype correlations have been reported for most LCA genes; for recent reviews see [1], [34] but not RD3 which mutations are amongst the rarest causes of the disease with two homozygous mutations reported in two consanguineous families [21], [35].…”

Leber congenital amaurosis, from darkness to light: An ode to Irene Maumenee

“…Eight mutations are currently known 4 . Phenotypically, RD3 mutations results in characteristic retinal layers disorganization at a young age and thinning of the plexiform layers as well as the inner nuclear, ganglion cell and nerve fiber layers 40 .…”

Advances in the genetics of eye diseases

“…Mutation in RD3 is a rare cause of LCA, previously shown to be associated with retinal degeneration [24]. Targets of ocular gene therapy thus far have been the retinopathies, treated through techniques of subretinal injection of adeno-associated viral or lentiviral vectors that carry the normal gene.…”