Clinical and Genetic Characteristics of Male Patients With RPGR-Associated Retinal Dystrophies

Talib, Mays; Schooneveld, Mary J. van; Thiadens, Alberta A H J; Fiocco, Marta; Wijnholds, Jan; Florijn, Ralph J.; Schalij‐Delfos, Nicoline E.; Genderen, Maria M. van; Putter, Hein; Cremers, Frans P.M.; Dagnelie, Gislin; Brink, Jacoline B. ten; Klaver, Caroline C W; Born, L. Ingeborgh van den; Hoyng, Carel B.; Bergen, Arthur A. B.; Boon, Camiel J F

doi:10.1097/iae.0000000000002125

Cited by 68 publications

(111 citation statements)

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“…A hyper-AF ring was found in six out of nine patients, including the CRD patient. Previous studies have shown that the hyper-AF ring correlates with the presence of the EZ band and demarcates the transition between healthy and affected retina [2,22,23]. The constriction of this hyper-AF ring in RP indicates disease progression, whereas, conversely, the expansion of the hyper-AF ring in CRD patients suggests disease progression [2,24].…”

Section: Discussionmentioning

confidence: 93%

“…Patients therefore typically present with symptoms of nyctalopia and peripheral visual field constriction, prior to symptoms of central vision loss. X-linked RP (XLRP) accounts for 5%-15% of all RP cases and is recognized as one of the most severe forms of RP [2,3]. Mutations in the RPGR gene are responsible for 70%-90% of all XLRP cases [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in the RPGR gene are responsible for 70%-90% of all XLRP cases [4][5][6]. Symptom onset in affected males starts in childhood years and is described to reach blindness within the 4th decade of life [2,7,8]. Despite the X-linked inheritance of RPGR, female carriers may also be affected by XLRP [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Other phenotypes caused by mutations in the RPGR gene include X-linked cone-rod dystrophies (CRD) and cone dystrophies (CD), in which degeneration predominantly affects cones, with or without the later involvement of rods [11]. Compared to XLRP, the age at onset is later in XL-CRD/CD, typically starting around the 4th decade of life, with initial symptoms being visual acuity loss, color vision defects, and variable photophobia [2,12].…”

Section: Introductionmentioning

confidence: 99%

“…The RPGR gene encodes the retinitis pigmentosa GTPase regulator (RPGR) protein and is able to express multiple isoforms through alternative splicing. The most common protein isoforms found in the retina are RPGR ORF15 and, to a lesser extent, the constitutive protein RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] [13,14]. The RPGR ORF15 transcript, which is believed to play a key role in intraflagellar transport processes, contains exon 1-14 and exon ORF15, which is formed by alternatively spliced exon 15 and intron 15 [15].…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Talib

Schooneveld

et al. 2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Talib

Schooneveld

et al. 2020

IJMS

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Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy

et al. 2020

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he gene GUCA1A (OMIM *600364) encodes the protein guanylate cyclase activating protein-1, a calciumsensitive protein integral to maintaining cyclic guanosine monophosphate levels in the outer segment of photoreceptors. Variants in this gene may be associated with a dominantly inherited cone dystrophy, largely by affecting calcium sensitivity. 1-4 In 2001, 3 families with variants in GUCA1A were reported in this journal. 2 Two families had the p.(Tyr99Cys) variant, with a relatively consistent phenotype. The third family had the p.(Pro50Leu) variant and exhibited a more variable phenotype (the proband had a cone dystrophy, but an affected relative had features consistent with retinitis pigmentosa). Since that publication, this family has undergone more detailed investigation, the results of which are described in the present report; we now associate their phenotype with a disease-causing variant in RPGR (OMIM *312610, coding for the retinitis pigmentosa [RP] GTPase regulator protein, thought to facilitate protein trafficking in photoreceptors) and not GUCA1A. Two of us (S.M.D. and A.B.) were also contributing authors of the original report. 2 Methods Clinical Examination and Imaging This study was performed from October 27, 2009, to May 23, 2019, after the original evaluation of the family, because the proband's daughter underwent a fundus examination (see Results). A fundal examination was performed at the slitlamp after mydriasis, and color fundus images and redfree images were taken from both eyes. The study was approved by Moorfields Eye Hospital and Northwest London Research Ethics Committee, and conformed to the tenets of the Declaration of Helsinki. 5 Participants provided written informed consent. IMPORTANCE As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. OBJECTIVE To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the gene GUCA1A was associated with a dominant retinal dystrophy, in light of new examination findings in the proband's daughter. DESIGN, SETTING, AND PARTICIPANTS A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband's daughter underwent fundus examination. MAIN OUTCOMES AND MEASURES Results of sequencing of X chromosome-linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of the RPGR gene. RESULTS A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (GRCh37 [hg19] x:38145160delT; NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant in GUCA1A was also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy. CONCLUSIONS AND RELEVANCE The phenoty...

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Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

et al. 2022

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Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression.Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. Using 17,394 smMIPs, we sequenced the coding regions of 105 iMD and AMD-associated genes and noncoding or regulatory loci, known pseudo-exons, and the mitochondrial genome in two test cohorts that were previously screened for variants in ABCA4.Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ''MD-smMIPs panel," enabling a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. Further analysis will identify known and novel

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Clinical and Genetic Characteristics of Male Patients With RPGR-Associated Retinal Dystrophies

Cited by 68 publications

References 41 publications

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

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

Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy

Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

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