scholarly journals Exploring the Variable Phenotypes of RPGR Carrier Females in Assessing their Potential for Retinal Gene Therapy

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 643 ◽  
Author(s):  
Anika Nanda ◽  
Anna P. Salvetti ◽  
Penny Clouston ◽  
Susan M. Downes ◽  
Robert E. MacLaren
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Phenotypic Variability ◽  
Genetic Mutation ◽  
X Inactivation ◽  
Autofluorescence Imaging ◽  
Genetic Sequencing ◽  
Pigmentary Retinopathy ◽  
Retinal Degenerations ◽  
Female Carriers

Inherited retinal degenerations are the leading cause of blindness in the working population. X-linked retinitis pigmentosa (XLRP), caused by mutations in the Retinitis pigmentosa GTPase regulator (RPGR) gene is one of the more severe forms, and female carriers of RPGR mutations have a variable presentation. A retrospective review of twenty-three female RPGR carriers aged between 8 and 76 years old was carried out using fundoscopy, autofluorescence imaging (AF), blue reflectance (BR) imaging and optical coherence tomography (OCT). Confirmation of the genetic mutation was obtained from male relatives or Sanger genetic sequencing. Fundus examination and AF demonstrate phenotypic variability in RPGR carriers. The genetic mutation appears indeterminate of the degree of change. We found four distinct classifications based on AF images to describe RPGR carriers; normal (N) representing normal or near-normal AF appearance (n = 1, 4%); radial (R) pattern reflex without pigmentary retinopathy (n = 14, 61%); focal (F) pigmentary retinopathy (n = 5, 22%) and; male (M) phenotype (n = 3, 13%). The phenotypes were precisely correlated in both eyes (rs = 1.0, p < 0.0001). Skewed X-inactivation can result in severely affected carrier females—in some cases indistinguishable from the male pattern and these patients should be considered for RPGR gene therapy. In the cases of the male (M) phenotype where the X-inactivation was skewed, the pattern was similar in both eyes, suggesting that the mechanism is not truly random but may have an underlying genetic basis.

scholarly journals Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ine Strubbe ◽  
Caroline Van Cauwenbergh ◽  
Julie De Zaeytijd ◽  
Sarah De Jaegere ◽  
Marieke De Bruyne ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Somatic Mosaicism ◽  
Retinal Disease ◽  
Hair Follicles ◽  
Disease Genes ◽  
Female Carrier ◽  
Autofluorescence Imaging ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Next Generation Sequencing Ngs

AbstractWe describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.

scholarly journals Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa

2021 ◽  
Vol 22 (5) ◽  
pp. 2374
Author(s):  
Laura Kuehlewein ◽  
Ditta Zobor ◽  
Katarina Stingl ◽  
Melanie Kempf ◽  
Fadi Nasser ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Genetic Testing ◽  
Retinitis Pigmentosa ◽  
Fundus Autofluorescence ◽  
Retinal Disease ◽  
New Drugs ◽  
Autofluorescence Imaging ◽  
Full Field ◽  
Tertiary Referral Center ◽  
The Right

In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.

Skewed X Inactivation of the Normal Allele in Fully Mutated Female Carriers Determines the Levels of FMRP in Blood and the Fragile X Phenotype

2005 ◽  
Vol 9 (3) ◽  
pp. 157-162 ◽  
Author(s):  
Raquel Martínez ◽  
Victoria Bonilla-Henao ◽  
Antonio Jiménez ◽  
Miguel Lucas ◽  
Carmen Vega ◽  
...  
Keyword(s):  
Fragile X ◽  
X Inactivation ◽  
Normal Allele ◽  
Skewed X Inactivation ◽  
Female Carriers

In vivo potency testing of subretinal rAAV5.hCNGB1 gene therapy in the Cngb1 knockout mouse model of retinitis pigmentosa

2021 ◽  
Author(s):  
Johanna E Wagner ◽  
Lena Zobel ◽  
Maximilian Joachim Gerhardt ◽  
Catherine R O'Riordan ◽  
Amy Frederick ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Knockout Mouse ◽  
Knockout Mouse Model

Retinal Transplantation, Stem Cell and Gene Therapy in Retinitis Pigmentosa

2021 ◽  
pp. 131-139
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Retinitis Pigmentosa ◽  
Retinal Dystrophy ◽  
Gene Replacement ◽  
Disease Genes ◽  
Functional Roles ◽  
Tunnel Vision ◽  
Hereditary Retinal Dystrophy ◽  
Cell And Gene Therapy

Retinitis pigmentosa is the most common hereditary retinal dystrophy which has marked clinical and genetic heterogeneity. Common presentations among this disorder include night blindness, tunnel vision, and subsequent progression to complete blindness respectively. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even within the same family, highlighting further levels of complexity. In recent years significant advancements have been made in the understanding of the pathogenesis of the disease and stem cell and gene replacement treatments have been proposed as potentially efficacious therapies. This review summarizes the clinical development of retinal stem cell and gene therapy.

scholarly journals Dose Range Finding Studies with Two RPGR Transgenes in a Canine Model of X-Linked Retinitis Pigmentosa Treated with Subretinal Gene Therapy

2020 ◽  
Vol 31 (13-14) ◽  
pp. 743-755 ◽  
Author(s):  
Chunjuan Song ◽  
Valérie L. Dufour ◽  
Artur V. Cideciyan ◽  
Guo-Jie Ye ◽  
Malgorzata Swider ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Dose Range ◽  
Canine Model ◽  
Range Finding

scholarly journals Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases

2016 ◽  
Vol 57 (7) ◽  
pp. 3211 ◽  
Author(s):  
Artur V. Cideciyan ◽  
Alejandro J. Roman ◽  
Samuel G. Jacobson ◽  
Boyuan Yan ◽  
Michele Pascolini ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Outcome Measure ◽  
High Luminance ◽  
Retinal Degenerations

Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa

2016 ◽  
Vol 12 (8) ◽  
pp. 2251-2260 ◽  
Author(s):  
Andrea Pensado ◽  
Francisco J. Diaz-Corrales ◽  
Berta De la Cerda ◽  
Lourdes Valdés-Sánchez ◽  
Ana Aramburu del Boz ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Retinitis Pigmentosa ◽  
Viral Vectors

scholarly journals Human Genes Escaping X-inactivation Revealed by Single Cell Expression Data

2018 ◽  
Author(s):  
Kerem Wainer Katsir ◽  
Michal Linial
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
Noncoding Rna ◽  
Phenotypic Variability ◽  
Cell Types ◽  
X Inactivation ◽  
Specific Expression ◽  
X Chromosomes ◽  
Human Genes ◽  
Cumulative Knowledge

AbstractBackgroundIn mammals, sex chromosomes pose an inherent imbalance of gene expression between sexes. In each female somatic cell, random inactivation of one of the X-chromosomes restores this balance. While most genes from the inactivated X-chromosome are silenced, 15-25% are known to escape X-inactivation (termed escapees). The expression levels of these genes are attributed to sex-dependent phenotypic variability.ResultsWe used single-cell RNA-Seq to detect escapees in somatic cells. As only one X-chromosome is inactivated in each cell, the origin of expression from the active or inactive chromosome can be determined from the variation of sequenced RNAs. We analyzed primary, healthy fibroblasts (n=104), and clonal lymphoblasts with sequenced parental genomes (n=25) by measuring the degree of allelic-specific expression (ASE) from heterozygous sites. We identified 24 and 49 candidate escapees, at varying degree of confidence, from the fibroblast and lymphoblast transcriptomes, respectively. We critically test the validity of escapee annotations by comparing our findings with a large collection of independent studies. We find that most genes (66%) from the unified set were previously reported as escapees. Furthermore, out of the overlooked escapees, 11 are long noncoding RNA (lncRNAs).ConclusionsX-chromosome inactivation and escaping from it are robust, permanent phenomena that are best studies at a single-cell resolution. The cumulative information from individual cells increases the potential of identifying escapees. Moreover, despite the use of a limited number of cells, clonal cells (i.e., same X-chromosomes are coordinately inhibited) with genomic phasing are valuable for detecting escapees at high confidence. Generalizing the method to uncharacterized genomic loci resulted in lncRNAs escapees which account for 20% of the listed candidates. By confirming genes as escapees and propose others as candidates from two different cell types, we contribute to the cumulative knowledge and reliability of human escapees.

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