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

Abstract

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations – predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38*) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided.

Control of the Nucleotide Cycle in Photoreceptor Cell Extracts by Retinal Degeneration Protein 3

“…The same authors further showed that RD3 loss in a mouse model correlates with an aggressive neuroblastoma cancer. These findings are, however, in disagreement with a previous study showing that inactivation of both RD3 alleles in LCA12 patients does not correlate with extraocular symptoms ( Perrault et al, 2013 ). Recently, RD3 immunoreactivity was detected in normal human cell types, in particular in epithelial cells ( Aravindan et al, 2017 ).…”

“…Mutations in RD3 of human patients correlate with the phenotypical characteristics of LCA12. Genetic screening approaches in worldwide collaborative efforts uncovered deletion and missense mutations in rd3 , which were predicted to result in complete loss of function ( Friedman et al, 2006 ; Perrault et al, 2013 ). Immunoprecipitation showed that RD3 binds to photoreceptor specific guanylate cyclases GC-E and GC-F and both proteins are not detectable in rods and cones of RD3 deficient mice ( Azadi et al, 2010 ).…”

RD3 loss dictates high-risk aggressive neuroblastoma and poor clinical outcomes

“…RD3 has been extensively studied in the context of eye degeneration. It has been shown that truncation mutations in this gene are responsible for photoreceptor degeneration and inflict early onset of vision loss in patients with Leber Congenital amaurosis 12 [ 16 , 19 , 23 – 25 ]. Although RD3 has been shown to be associated with the leukemia gene product PML [ 17 ], the crucial role of RD3 in cancer biology has been overlooked.…”

Impaired Association of Retinal Degeneration-3 with Guanylate Cyclase-1 and Guanylate Cyclase-activating Protein-1 Leads to Leber Congenital Amaurosis-1

“…This condition prevents targeting of GC1 and leads to LCA1. Perrault et al (40) evaluated RD3 mutation in patients with LCA or early-onset severe retinal degeneration and identified three Rd3 mutations as follows: c.112C.T, c.136G.T, and a 2-bp deletion in c.137-138. The LCA12 phenotype strongly resembles LCA1.…”