Retinitis Pigmentosa (Non-syndromic)

Tsang, Stephen H.; Sharma, Tarun

doi:10.1007/978-3-319-95046-4_25

Cited by 54 publications

(51 citation statements)

References 2 publications

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“…To date, nearly 100 unique genes have been implicated in RP pathogenesis, with significant overlap among genes shared with RP and the related IRDs including Leber's Congenital Amaurosis (LCA), cone-rod dystrophy, and macular dystrophy [3]. Inheritance patterns vary from autosomal dominant [6,7] (15-35%) and autosomal recessive [8,9] (15-20%), to X-linked [10,11] (10-15%) and sporadic (30%) [11]. Mutations in the NRL and NR2E3 genes encoding rod-specific transcription factors exemplify this diversity, as autosomal dominant [12,13], autosomal recessive [14,15], and sporadic [16] mutations have been implicated in RP and the related IRD, enhanced S-cone syndrome (ESCS).…”

Section: Genetic Heterogeneity Of Retinitis Pigmentosamentioning

confidence: 99%

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Moore

Skowronska‐Krawczyk

Chao³

2020

JCM

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Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper ( NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

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Section: Genetic Heterogeneity Of Retinitis Pigmentosamentioning

confidence: 99%

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Moore

Skowronska‐Krawczyk

Chao³

2020

JCM

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“…Changes at any step of the photocycle can impair the visual cycle and therefore lead to numerous visual disorders. [8] Ah otspot for mutations of the wild type sequence is amino acid G90. Depending on the nature of the introduced amino acid, mutations of G90 can either lead to the most common human-inherited retinal dystrophy night blindness disease called retinitis pigmentosa (RP) [8] or congenital stationary night blindness (CSNB) [9,10] (G90V and G90D,r espectively).…”

Section: Introductionmentioning

confidence: 99%

“…[8] Ah otspot for mutations of the wild type sequence is amino acid G90. Depending on the nature of the introduced amino acid, mutations of G90 can either lead to the most common human-inherited retinal dystrophy night blindness disease called retinitis pigmentosa (RP) [8] or congenital stationary night blindness (CSNB) [9,10] (G90V and G90D,r espectively). CSNB is an on-progressive inherited retinal disorder, which was found to be genetically and clinically heterogeneous.First symptoms of this disease are the reduction of dim and night vision, problems with the adaptation to darkness and in some cases loss of the general visual acuity.C SNB exhibits an overlapping phenotype with visual diseases such as RP, progressive rod-cone dystrophy and acquired night blindness (vitamin Adeficiency) but in contrast to these diseases,CSNB is non-progressive.…”

Section: Introductionmentioning

confidence: 99%

Light Dynamics of the Retinal‐Disease‐Relevant G90D Bovine Rhodopsin Mutant

et al. 2020

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The RHO gene encodes the G‐protein‐coupled receptor (GPCR) rhodopsin. Numerous mutations associated with impaired visual cycle have been reported; the G90D mutation leads to a constitutively active mutant form of rhodopsin that causes CSNB disease. We report on the structural investigation of the retinal configuration and conformation in the binding pocket in the dark and light‐activated state by solution and MAS‐NMR spectroscopy. We found two long‐lived dark states for the G90D mutant with the 11‐cis retinal bound as Schiff base in both populations. The second minor population in the dark state is attributed to a slight shift in conformation of the covalently bound 11‐cis retinal caused by the mutation‐induced distortion on the salt bridge formation in the binding pocket. Time‐resolved UV/Vis spectroscopy was used to monitor the functional dynamics of the G90D mutant rhodopsin for all relevant time scales of the photocycle. The G90D mutant retains its conformational heterogeneity during the photocycle.

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Section: Introductionmentioning

confidence: 99%

“…Retinitis pigmentosa (RP, MIM 268000) is a group of inherited retinal degenerative diseases characterized by night blindness due to the progressive loss of rod photoreceptors, followed by complete blindness due to the further loss of cones (Hamel 2006, Tsang and Sharma 2018). X linked retinitis pigmentosa (XLRP) represents the most severe and prevalent form owing to its early onset and severity of progress (Tee et al 2018, Tsang and Sharma 2018). To date, six loci have been associated with XLRP, yet only three genes have been identified (Lyraki et al 2016, Ferrante et al 2001, Schwahn et al 1998, Meindl et al 1996), among which the retinitis pigmentosa GTPase regulator ( RPGR ) gene [MIM 312610] accounts for 70-90% of XLRP and 15-20% of simplex RP cases, making it one of the most common causes of RP (Parmeggiani et al 2017, Khanna 2018).…”

Section: Introductionmentioning

confidence: 99%

Novel missense mutation E585K in retinitis pigmentosa leads to compromisedRPGRsplicing diversity

Liu

Wan

Ren

et al. 2020

Preprint

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23Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of 24 X-linked retinitis pigmentosa (RP). Herein we used whole-exome sequencing to screen 25 possible novel RPGR mutations in RP patients, and identified a novel missense mutation 26 E585K in a patient with early onset but slow disease progression, and a frameshift deletion 27 E998Gfs*78 in a patient with RP sine pigmento and high myopia. Intriguingly, bioinformatic 28 analysis indicated that E585K probably affected RPGR RNA splicing instead of the protein 29 sequence directly. Mini-gene assays in 293T cells revealed that splicing events of the E585K 30 mutant were found to be also exist in wildtype, but with a shifted pattern. In the E585K mini-31 gene usage of an upstream alternative 5′ splice site (5′ ss) of exon 14 was enhanced, and other 32 splicing events were suppressed, including the canonical 5′ ss of exon 14, skipping of exon 33 14/15 and retention of intron 14. As a result, RPGR splicing products of the E585K mini-gene 34 were predominated by transcripts containing a 4-bp deletion, with a small fraction of in-frame 35 transcripts containing a retended intron 14, which might explain the slow disease progression 36 in the patient carrying the mutation. RNA-Seq analysis further confirmed existence of these 37 splicing events in endogenous RPGR RNA in human retina, pointing to compromised splicing 38 diversity in the E585K mutant. Our findings thus added to the understanding of genotype-39 phenotype correlation in RP, and suggested that compromised RPGR splicing diversity might 40 play a role in molecular mechanism of the disease. 41

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Retinitis Pigmentosa (Non-syndromic)

Cited by 54 publications

References 2 publications

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

Light Dynamics of the Retinal‐Disease‐Relevant G90D Bovine Rhodopsin Mutant

Novel missense mutation E585K in retinitis pigmentosa leads to compromisedRPGRsplicing diversity

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