Disease expression in X-linked retinitis pigmentosa caused by a putative null mutation in the RPGR gene

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia 19104, USA.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.66). 09/1997; 38(10):1983-97.
Source: PubMed

ABSTRACT To determine the disease expression in X-linked retinitis pigmentosa (XLRP) caused by a putative null mutation in the RPGR (retinitis pigmentosa GTPase regulator) gene.
In a family with XLRP, haplotype analysis was performed with polymorphic microsatellite markers from the Xp chromosomal region, and genomic polymerase chain reaction sequencing was used to identify sequence variations in the RPGR gene. Hemizygotes and heterozygotes were evaluated clinically and with visual function tests. Optical coherence tomography (OCT) was performed on heterozygotes. Postmortem donor retinas from a heterozygote were examined by microscopy and immunocytochemistry.
X-linked inheritance was confirmed by haplotype analysis using Xp markers. Sequence analysis of the RPGR gene identified a single base pair change, a G-->T transversion, that converts codon 52 GGA (Gly) to TGA (stop codon); the mutation segregates with the disease. A hemizygote in the third decade of life had barely measurable rod function and severely impaired cone function that diminished further over a 7-year interval. Heterozygotes varied in degree of disease expression from mild to severe. Perimetry showed loci with normal rod and cone sensitivity interspersed with loci having either equal rod and cone dysfunction or rod > cone dysfunction. Electroretinographic photoreceptor responses had equal reductions in rod and cone maximal amplitude. OCT cross sectional reflectance images of retinal regions with severe dysfunction showed reduced thickness of the retina and retinal pigment epithelium-choriocapillaris (RPE-CC) complex and increased reflections posteriorly. Regions with mild dysfunction showed similar OCT findings but with preserved retinal thickness. Retinal histopathology in a heterozygote revealed loss of photoreceptors throughout, with retention of only a few islands of cones with tiny or absent outer segments and rods lacking outer segments.
This RPGR gene mutation, in its mildest expression in heterozygotes, causes a relatively equal disturbance of rod and cone photoreceptor function. Detectable structural change by OCT at the level of the RPE-CC can be present in patches of retina with minimal functional disturbance. More advanced disease stages in heterozygotes show greater rod than cone dysfunction, and the end stage in hemizygotes and heterozygotes is that of typical RP, with only barely detectable cone function from residual cones in a thinned retina with abnormal RPE and choriocapillaris.

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Available from: Artur Cideciyan, Aug 23, 2015
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    • "RPGR overexpression in the WT retina will also inform as to whether similar gene therapy intervention could be safely considered for some carrier female patients. Finally, pursuing detailed phenotypic characterization of XLRP patients (Jacobson et al. 1997; Lorenz et al. 2003; Aleman et al. 2007; Huang et al. 2012) is necessary to establish valid outcome measures of therapeutic efficacy for future human clinical trials. "
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    ABSTRACT: X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is a severe and early onset form of retinal degeneration, and no treatment is currently available. Recent evidence in two clinically relevant canine models shows that adeno-associated viral (AAV)-mediated RPGR gene transfer to rods and cones can prevent disease onset and rescue photoreceptors at early- and mid-stages of degeneration. There is thus a strong incentive for conducting long-term, preclinical efficacy and safety studies, while concomitantly pursuing the detailed phenotypic characterization of XLRP disease in patients that may benefit from such corrective therapy.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(2). DOI:10.1101/cshperspect.a017392 · 7.56 Impact Factor
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    • "We also found structural changes in SD-OCT images, in the form of thinning of the outer retinal layers within the central 30 in all XLRP carriers. Previous qualitative OCT assessments have reported retinal layer thinning in studies consisting of 2 carriers (Jacobson et al., 1997) and 5 carriers (Vingolo et al., 2006), in agreement with our findings, however in another study of 3 carriers, retinal thickness was observed to be normal (Genead et al., 2010). The finding of thinning of the outer retinal layers in XLRP carriers is consistent with reports of retinal thinning in RP (Hood et al., 2009), as well as thinning of the outer nuclear layer found in a canine model of XLRP carriers (Beltran et al., 2009). "
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    ABSTRACT: The aim of this study was to investigate visualization of the tapetal-like reflex using current imaging modalities and evaluate SD-OCT changes in known carriers of X-linked retinitis pigmentosa (XLRP); the objective being the development of an optimal protocol for clinicians to identify carriers. Ten XLRP carriers (19 eyes) were examined using color fundus photography, 488 nm reflectance (488-R), near-infrared reflectance (NIR-R), autofluorescence (AF) and spectral-domain optical coherence tomography (SD-OCT) imaging (Spectralis SLO-OCT, Heidelberg). Horizontal line scans through the fovea were acquired in all subjects and in a group of 10 age-similar controls. Peripheral SD-OCT scans (extending to 27.5° eccentricity) were also acquired in both eyes of 7 carriers. MP-1 microperimetery (10-2 pattern; Nidek) was performed in one eye of each carrier. For the XLRP carriers, a tapetal reflex was observed with all imaging modalities in 8 of 19 eyes. It had the same retinal location on color fundus, 488-R and NIR-R imaging but a different location on AF. The tapetal reflex was most easily detected in 488-R images. The horizontal foveal SD-OCT scans were qualitatively normal, but measurements showed significant outer retinal layer thinning in all eyes. Additionally, the 14 eyes with peripheral SD-OCTs demonstrated patchy loss of the inner segment ellipsoid band. Microperimetry exhibited patchy visual sensitivity loss in 9 eyes. Full field ERGs were variable, ranging from normal to severely abnormal rod and cone responses. Our findings suggest that an optimal protocol for identifying carriers of XLRP should include 488-R imaging in a multimodal approach. Peripheral SD-OCT imaging and central retinal layer quantification revealed significant structural abnormalities.
    Experimental Eye Research 05/2013; 113. DOI:10.1016/j.exer.2013.05.003 · 3.02 Impact Factor
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    • "Evidence also indicates that the components of the RPGRIP1 complex, PrBP/d and RPGR, apparently associate or form high-order complexes with Rab13, Arl2, H-Ras, Rheb, Rho6, Rab8a, nephrocystin-5 (NPHP5) or CEP290/nephrocystin-6 (NPHP6) (Chang et al., 2006; Hanzal-Bayer et al., 2002; Murga- Zamalloa et al., 2010; Otto et al., 2005). In addition, genetic modifiers modulate the expression of XlRP3, because similar mutations in Rpgr can cause discordant phenotypes in the human (Banin et al., 2007; Walia et al., 2008), the penetrance of the disease varies greatly among species (Brunner et al., 2010; Hong et al., 2000; Jacobson et al., 1997; Zeiss et al., 1999; Zhang et al., 2002), allelic heterogeneity in XlRP3 differentially affect rod and cone photoreceptor neurons (Demirci et al., 2002; Sharon et al., 2003; Yang et al., 2002), and RPGRIP1, RPGRIP1L and NPHP5 (IQCB1) can act as genetic modifiers of the clinical expression of XlRP3 in the human (Fahim et al., 2011). Collectively, these data hint to a model where the combinatorial coding by various accessory proteins contributes in a cell-context dependent manner to the dynamic composition or multifunctional properties of the RPGRIP1-RPGR interactome and development of selective celltype phenotypes upon mutations in components of the RPGRIP1 assembly complex. "
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    Biology Open 02/2012; 1(2):140-60. DOI:10.1242/bio.2011489 · 2.42 Impact Factor
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