Researchers based at the UCL Institute of Ophthalmology, London and in Moorfields Eye Hospital, also in London, have shown clinical features in two pedigrees with dominantly inherited retinopathy in the “RGR” gene, encoded by a RPE-retinal G protein-coupled receptor protein. A previously reported frame-shifting mutation, c.836dupG (p.Ile280Asn*78) was identified in the terminal exon of the RGR gene. Clinical data in families suggest a variable and slow degeneration of the RPE, additionally suggesting a single ancestral mutational event underlying families. The analysis suggests that haplo-insufficiency may be too common to be responsible for the inherited retinal degeneration, leading the UK team to support an hypothesis of a toxic or gain-of-function effect.
Inheritable dystrophies present with variable clinical features, and have high genetic and allelic heterogeneity – disease-causing variants in inherited retinal degenerations have more than 300 genes (https://sph.uth.edu/retnet/). RPE-retinal G-protein-coupled receptor (RGR) is a rhodopsin homolog gene found in cells adjacent to retinal photoreceptor cells. The protein preferentially binds all-trans retinal rather than 11-cis retinal – photons of light converting all-trans retinal within RGR to 11-cis retinal, while the reverse isomerization reaction occurs in rhodopsin in photoreceptor cells. Patient samples of the research were used by next generation sequencing (NGS) and whole genome sequencing (WGS), in addition to identify phenotypic data of visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). There appears to be only one-disease causing mutation in RGR. Nine heterozygous mutation carriers were identified in two families – 4 carriers were asymptomatic and 5 carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyper-autofluorescence in mild cases and ERG showed moderate-to-severe rod–cone dysfunction in two symptomatic carriers.
As highlighted by the research commentary, the “report exemplified the success of the unbiased approaches of WGS and NGS in the molecular diagnosis of a highly genetically heterogeneous disorder, such as retinal dystrophy. The clinical features suggested a variable severity of retinopathy consequent upon heterozygosity of a specific allele of the RGR gene. The slow progression of this retinopathy and possible primary involvement of the RPE make this disorder tractable to potential therapeutic interventions.” As the research indicates a dominant allele pathology, the therapeutic rescue may serve several potential approaches, such as RNAi or CRISPR technologies.