RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features

Abstract

This study describes the clinical, genetic, and histopathological features in patients with RPGR-associated retinal dystrophies. Nine male patients from eight unrelated families underwent a comprehensive ophthalmic examination. Additionally, the histopathology of the right eye from a patient with an end-stage cone-rod-dystrophy (CRD)/sector retinitis pigmentosa (RP) phenotype was examined. All RPGR mutations causing a CRD phenotype were situated in exon ORF15. The mean best-corrected visual acuity (BCVA, decimals) was 0.58 (standard deviation (SD)): 0.34; range: 0.05–1.13); and the mean spherical refractive error was −4.1 D (SD: 2.11; range: −1.38 to −8.19). Hyperautofluorescent rings were observed in six patients. Full-field electroretinography responses were absent in all patients. The visual field defects ranged from peripheral constriction to central islands. The mean macular sensitivity on microperimetry was 11.6 dB (SD: 7.8; range: 1.6–24.4) and correlated significantly with BCVA (r = 0.907; p = 0.001). A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. Our study demonstrates the highly variable phenotype found in RPGR-associated retinal dystrophies. Therapies should be applied at the earliest signs of photoreceptor degeneration, prior to the remodeling of the inner retina.

Spectrum of Disease Severity in Patients With X-Linked Retinitis Pigmentosa Due to RPGR Mutations

“… 58 This finding is consistent with two previous studies that reported no case of CME in patients with RPGR -RP. 9 , 35 Moreover, the lower frequency of CME observed in patients with X-linked RP (7.1%) compared to autosomal forms reported in our previous study 58 strongly suggest that the incidence of CME in RP varies according to the mutated gene. On the contrary, the frequency of ERM and VMT in patients with RPGR- RP was similar to that observed in our overall RP cohort (ERM = 25% in RPGR -RP vs. 19.8% in RP; VMT = 2.5% in RPGR -RP vs. 5% in RP).…”

“… 32 The disease severity associated with ORF15 variants could be attributed to the presumed gain-of-function or dominant-negative effect of the resulting protein product, as previously suggested. 28 , 30 , 35 , 40 Variants in ORF15 are mostly small deletions or duplications leading to frameshift changes. Because ORF15 is the terminal exon of the RPGR ORF15 transcript, the stop or frame-shifting variants are, in principle, not subject to nonsense-mediated mRNA decay, but can be expected to lead to the synthesis of presumably dysfunctional protein products.…”

“…31,32 A common ground was found instead regarding RPGR variants located toward the 3 end of ORF15, which were more frequently associated with milder XL Cone Rod Dystrophy (CRD) / XL Cone Dystrophy (CD) phenotypes. 25,30,[33][34][35] Finally, some RPGR variants in exons 1 to 14 were reported in patients with RP presenting progressive hearing loss, sinusitis, and chronic recurrent respiratory tract infections, [36][37][38] in line with the more widespread expression of the RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] isoform and its essential ciliary function in other organs apart from retina. 39,40 In this study, we report the clinical and genetic findings in a cohort of 48 male patients of Italian origin with XLRP caused by variants in RPGR.…”

Cone Dystrophy Associated with a Novel Variant in the Terminal Codon of the RPGR-ORF15

“…It is not known why the RPGR mutations result in two contrasting disorders. It seems that the phenotype depends on the location of the mutation: Mutations in the exons 1–14 and the proximal part of the ORF15 exon usually result in retinitis pigmentosa, while the mutations in the distal end of the ORF15 exon cause cone/cone-rod dystrophy [ 11 , 29 , 42 , 43 , 44 ]. There is however a watershed zone of approximately 100 aminoacids between the two regions, where mutations can result in either phenotype, even within the same family [ 29 ], the reasons for which are not understood.…”

Sector Retinitis Pigmentosa: Extending the Molecular Genetics Basis and Elucidating the Natural History

“…There are 6 previously reported disease-causing genes: rhodopsin (AD: RHO : Online Mendelian Inheritance in Man [OMIM] entry 180380; n = 70 cases), 4 , 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 usherin (AR: USH1C : OMIM 605242; n = 2) 2 ; cadherin 23 (AR: CDH23 , OMIM 605516; n = 1) 18 ; retinol dehydrogenase 5 (AR: RDH5 , OMIM 601617; n = 1) 19 ; arrestin (AR: SAG , OMIM 181031; n = 1) 20 ; and more recently, RP GTPase regulator gene (XL, RPGR , OMIM 312610; n = 2). 4 , 21 All previously reported sector RP-causing variants are summarized in Supplemental Table 1 . Currently there are ongoing efforts to develop and approve novel therapeutic options for diseases caused by RPGR -RP and RHO -RP.…”