To characterize the molecular defects in two x-linked retinitis pigmentosa (RP) families. We hypothesized that different RPGR mutations result in distinct RP phenotypes.
Observational case series.
Fifteen members in family I and three members in family II were evaluated. Full ophthalmic evaluations were done. Linkage analyses were performed and likelihood of odds scores (LOD score) were calculated. For mutation analyses, we used dHPLC and automated sequencing.
Two novel RPGR mutations were identified in the two families; a Glu 414 (2-bp del) frameshift mutation in family I and an IVS 2-1 (g to a) splice site mutation in family II. All male family members in family I were severely affected by RP but maintained central visual acuities until their 50s and did not develop a bull's eye maculopathy. The female phenotype was highly variable. Some of the carriers exhibited a severe phenotype, one female displayed an asymmetric phenotype, and other carriers were asymptomatic. All members with the RPGR frameshift mutation exhibited rod-cone electroretinograms abnormalities, whereas five members had hearing loss. Male members of family II were severely affected, with early visual acuity loss, central scotomas, and bull's eye maculopathy. The female family members were asymptomatic but displayed cone-rod electroretinograms changes. There was no hearing loss.
Different RPGR mutations lead to distinct RP phenotypes, with a highly variable inter- and intrafamilial phenotypic spectrum of disease that is associated with the type of mutation in RPGR and nonrandom X chromosome inactivation, respectively.
"Recent reports have suggested that RPGR may contribute to the biogenesis and maintenance of photoreceptor cilia and the transitional zone of motile cilia (Murga- Zamalloa et al. 2010a; Gakovic et al. 2011; Ghosh et al. 2011). Consistent with this role is the occurrence of hearing dysfunction, respiratory infections, and cilia dyskinesis in some rare cases of syndromic RPGR-XLRP (van Dorp et al. 1992; Iannaccone et al. 2003; Koenekoop et al. 2003; Zito et al. 2003; Iannaccone et al. 2004; Moore et al. 2006; Bukowy-Bieryllo et al. 2013). "
[Show abstract][Hide abstract] 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 · 9.47 Impact Factor
"BEM is a distinctive macular phenotype characterized by annular RPE atrophy with central sparing of the fovea. Initially, BEM was described in association with chloroquine retinopathy  but has been associated with various inherited retinal degenerations, also with RP [12-14]. However, in retinitis pigmentosa is not a common feature, and therefore, it is remarkable that nearly all patients with PRCD mutations reported in the literature carry this phenotypic characteristic. "
[Show abstract][Hide abstract] ABSTRACT: Progressive rod-cone degeneration (PRCD) is a canine form of autosomal recessive photoreceptor degeneration and serves as an animal model for human retinitis pigmentosa (RP). To date, only two RP-causing mutations of the PRCD gene have been reported in humans. We found a novel mutation in PRCD (c.52C>T, p.R18X) in three siblings affected by RP and present detailed morphologic and functional parameters.
A complete ophthalmological examination was performed including psychophysical tests (best-corrected visual acuity, Lanthony Panel D-15 color vision test, and visual field) and electrophysiology (ganzfeld and multifocal electroretinogram). Additionally, color and infrared fundus photography, autofluorescence, and spectral domain optical coherence tomography recordings were performed. Genomic DNA of the three affected individuals was analyzed with high-throughput sequencing for all RP-related genes in a diagnostic set-up.
We identified a novel homozygous mutation in PRCD (c.52C>T, p.R18X) with diagnostic high-throughput panel sequencing. All three patients showed an advanced stage of retinitis pigmentosa with reduced visual acuity (mean: 20/80), small residual visual fields (mean for target III4e: 1134.35 deg(2)), and non-detectable electrophysiological responses. Myopia, posterior subcapsular cataract, bone spicule-like pigmentation, and attenuated arterioles were typical findings. Interestingly, bull's eye maculopathy due to patchy retinal pigment epithelium atrophy was also present in all patients. The mean central retinal thickness observed in optical coherence tomography was 148 µm.
The identification of a third mutation in PRCD confirms its role in the pathogenesis of RP. Clinical findings were in line with the morphological changes observed in previous studies. Bull's eye maculopathy seems to be a hallmark of RP due to mutations in the PRCD gene.
"In addition, several families with cone-rod dystrophy have been reported with mutations in RPGR, all of them in ORF15 downstream of ORF15 codon 445 , , , . There is also evidence that some mutations in RPGR are more likely to be penetrant in female carriers while other mutations cause disease only in hemizygous males , , . "
[Show abstract][Hide abstract] ABSTRACT: Mutations in RPGR account for over 70% of X-linked retinitis pigmentosa (XlRP), characterized by retinal degeneration and eventual blindness. The clinical consequences of RPGR mutations are highly varied, even among individuals with the same mutation: males demonstrate a wide range of clinical severity, and female carriers may or may not be affected. This study describes the phenotypic diversity in a cohort of 98 affected males from 56 families with RPGR mutations, and demonstrates the contribution of genetic factors (i.e., allelic heterogeneity and genetic modifiers) to this diversity. Patients were categorized as grade 1 (mild), 2 (moderate) or 3 (severe) according to specific clinical criteria. Patient DNAs were genotyped for coding SNPs in 4 candidate modifier genes with products known to interact with RPGR protein: RPGRIP1, RPGRIP1L, CEP290, and IQCB1. Family-based association testing was performed using PLINK. A wide range of clinical severity was observed both between and within families. Patients with mutations in exons 1-14 were more severely affected than those with ORF15 mutations, and patients with predicted null alleles were more severely affected than those predicted to make RPGR protein. Two SNPs showed association with severe disease: the minor allele (N) of I393N in IQCB1 (p = 0.044) and the common allele (R) of R744Q in RPGRIP1L (p = 0.049). These data demonstrate that allelic heterogeneity contributes to phenotypic diversity in XlRP and suggest that this may depend on the presence or absence of RPGR protein. In addition, common variants in 2 proteins known to interact with RPGR are associated with severe disease in this cohort.
PLoS ONE 08/2011; 6(8):e23021. DOI:10.1371/journal.pone.0023021 · 3.23 Impact Factor
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