Novel mutations in the RS1 gene in Japanese patients with X-linked congenital retinoschisis.
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SUBMITTER: Kondo H
PROVIDER: S-EPMC6325138 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Novel mutations in the <i>RS1</i> gene in Japanese patients with X-linked congenital retinoschisis.
Kondo Hiroyuki H Oku Kazuma K Katagiri Satoshi S Hayashi Takaaki T Nakano Tadashi T Iwata Akiko A Kuniyoshi Kazuki K Kusaka Shunji S Hiyoshi Atsushi A Uchio Eiichi E Kondo Mineo M Oishi Noriko N Kameya Shuhei S Mizota Atsushi A Naoi Nobuhisa N Ueno Shinji S Terasaki Hiroko H Morimoto Takeshi T Iwaki Masayoshi M Yoshitake Kazutoshi K Iejima Daisuke D Fujinami Kaoru K Tsunoda Kazushige K Shinoda Kei K Iwata Takeshi T
Human genome variation 20190108
X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the <i>RS1</i> gene. We have identified 37 different mutations in the <i>RS1</i> gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations. ...[more]
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Project description:PURPOSE: To determine the clinical features and to identify mutations in the retinoschisis gene (RS1) in ten patients with X-linked retinoschisis (XLRS). METHODS: Ten male patients from nine Polish families were included in this study. Ophthalmologic examinations, including optical coherence tomography (OCT) and full-field electroretinography (ERG), were performed in all affected boys. The entire coding region encompassing six exons of the RS1 gene was amplified with PCR and directly sequenced in all the patients. RESULTS: All affected individuals showed typical retinoschisis signs and symptoms, and all appeared to have a mutation in the RS1 gene. Seven different mutations were identified, including two novel missense substitutions: c.176G>C (p.Cys59Ser), c.451T>A (p.Tyr151Asp); one novel nonsense substitution: c.218C>A (p.Ser73*); and one novel frameshift mutation: c.354_355delCA (p.Asp118Glufs*2). We also found two missense substitutions that had been previously described: c.214G>A (p.Glu72Lys) and c.626G>T (p.Arg209Leu) and one known splice site mutation in intron 5: c.522+1G>T (IVS5+1G>T). CONCLUSIONS: This study provides the first molecular genetic characteristics of patients with juvenile retinoschisis from the previously unexplored Polish population. We investigated the molecular background of XLRS in ten boys. The present study reports for the first time four novel mutations, including two missense substitutions, one nonsense substitution, and one frameshift deletion. One of these substitutions and 2-bp deletion created stop codons. Moreover, we described three substitutions that had been previously reported (one is a splicing mutation). Further genetic characterization of Polish patients with XLRS will be helpful in understanding the worldwide spectrum of RS1 mutations. Despite the mutation heterogeneity found in a small group of our patients, they presented a relatively uniform clinical picture. Identifying the causative mutation is helpful in confirming diagnosis and counseling, but cannot provide prognostic data.
| S-EPMC3534142 | biostudies-literature
Project description:To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon 3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon 6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS.
| S-EPMC3573736 | biostudies-literature
Project description:PurposeX-linked retinoschisis is a retinal dystrophy caused by mutations in the RS1 gene in Xp22.1. These mutations lead to schisis (splitting) of the neural retina and subsequent reduction in visual acuity in affected men (OMIM # 312700). The aim of this study was to identify the RS1 gene mutations in a cohort of Chinese patients with X-linked retinoschisis, and to describe the associated phenotypes.MethodsPatients and unaffected individuals from 16 unrelated families underwent detailed ophthalmic examinations. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. All exons including the exon-intron boundaries of the RS1 gene, were amplified by PCR and the products were analyzed by direct sequencing. Long-range PCR followed by DNA sequencing was used to define the breakpoints of the large deletion.ResultsSixteen male individuals from 16 families were diagnosed with retinoschisis by clinical examination. The median age at review was 13.2 years (range: 5-34 years); the median best-corrected visual acuity upon review was 0.26 (range 0.02-1.0). Foveal schisis was found in 82.8% of the eyes (24/29) while peripheral schisis was present in 27.5% of the eyes (8/29). Sequencing of the RS1 gene identified 16 mutations, nine of which were novel. The mutations included eight missense mutations, all located in exons 4-6 (50.0%), two nonsense mutations (12.5%), four small deletions or insertions (25.0%), one splice site mutation (6.25%), and one large genomic deletion that included exon1 (6.25%).ConclusionsThe mutations found in our study broaden the spectrum of RS1 mutations. The identification of the specific mutation in each pedigree will allow future determination of female carrier status for genetic counseling purposes.
| S-EPMC3913487 | biostudies-literature
Project description:X-linked juvenile retinoschisis (XLRS) is a vitreoretinal dystrophy characterized by schisis (splitting) of the inner layers of the neuroretina. Mutations within the retinoschisis (RS1) gene are responsible for this disease. The mutation spectrum consists of amino acid substitutions, splice site variations, small indels, and larger genomic deletions. Clinically, genomic deletions are rarely reported. Here, we characterize two novel full exonic deletions: one encompassing exon 1 and the other spanning exons 4-5 of the RS1 gene. We also report the clinical findings in these patients with XLRS with two different exonic deletions.Unrelated XLRS men and boys and their mothers (if available) were enrolled for molecular genetics evaluation. The patients also underwent ophthalmologic examination and in some cases electroretinogram (ERG) recording. All the exons and the flanking intronic regions of the RS1 gene were analyzed with direct sequencing. Two patients with exonic deletions were further evaluated with array comparative genomic hybridization to define the scope of the genomic aberrations. After the deleted genomic region was identified, primer walking followed by direct sequencing was used to determine the exact breakpoints.Two novel exonic deletions of the RS1 gene were identified: one including exon 1 and the other spanning exons 4 and 5. The exon 1 deletion extends from the 5' region of the RS1 gene (including the promoter) through intron 1 (c.(-35)-1723_c.51+2664del4472). The exon 4-5 deletion spans introns 3 to intron 5 (c.185-1020_c.522+1844del5764).Here we report two novel exonic deletions within the RS1 gene locus. We have also described the clinical presentations and hypothesized the genomic mechanisms underlying these schisis phenotypes.
| S-EPMC3820431 | biostudies-literature
Project description:PurposeX-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. This study aimed to identify the underlying genetic defect in a Chinese family with XLRS.MethodsThe proband underwent complete ophthalmic examinations, including fundus examination, fundus autofluorescence, and optical coherence tomography. DNA extracted from proband and his younger brother was screened for mutations in RS1 gene. The detected RS1 mutation was tested in all available family members and 200 healthy controls.ResultsReduced visual acuity, spoke-wheel pattern at the fovea, and split retina were observed in the proband. A novel frameshift mutation c.206-207delTG in the RS1 gene, leading to a truncated protein (p.L69fs16X), was identified in the proband and his younger brother. This mutation was not found in any unaffected member or in the healthy controls. The mother of the proband was hemizygous for this mutant allele.ConclusionsWe identified a novel causative mutation of RS1 in a Chinese family with XLRS. This finding expands the mutation spectrum of RS1 and provides evidence for a phenotype-genotype study in XLRS.
| S-EPMC4274291 | biostudies-literature
Project description:X-linked juvenile retinoschisis is a heritable condition of the retina in males caused by mutations in the RS1 gene. Still, the cellular function and retina-specific expression of RS1 are poorly understood. To address the latter issue, we characterized the minimal promoter driving expression of RS1 in the retina. Binding site prediction, site-directed mutagenesis, and reporter assays suggest an essential role of two nearby cone-rod homeobox (CRX)-responsive elements (CRE) in the proximal -177/+32 RS1 promoter. Chromatin immunoprecipitation associates the RS1 promoter in vivo with CRX, the coactivators CBP, P300, GCN5 and acetylated histone H3. Transgenic Xenopus laevis expressing a green fluorescent protein (GFP) reporter under the control of RS1 promoter sequences show that the -177/+32 fragment drives GFP expression in photoreceptors and bipolar cells. Mutating either of the two conserved CRX binding sites results in strongly decreased RS1 expression. Despite the presence of sequence motifs in the promoter, NRL and NR2E3 appear not to be essential for RS1 expression. Together, our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression.
| S-EPMC2582616 | biostudies-literature
Project description:BACKGROUND:To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n?=?9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging. METHODS:The Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and genetic analysis. Nine affected patients were identified across 3 generations of an XLRS1 pedigree. DNA sequencing was performed for each patient, one carrier female and one unaffected relative. Pedigree mapping revealed a further 4 affected males. RESULTS:All affected patients had a history of reduced visual acuity and dyschromatopsia; however, the severity of phenotype varied widely between the nine affected subjects. The stage of disease was classified as previously described. Phenotypic severity was not linearly correlated with age. A novel RS1 (Xp22.2) mutation was detected (NM_000330: c.413C?>?A) resulting in a p.Thr138Asn substitution. Protein modelling demonstrated a change in higher order protein folding that is likely pathogenic. CONCLUSIONS:This family has a novel gene mutation in RS1 with clinical evidence of XLRS1. A proportion of the older generation has developed end-stage macular atrophy; however, the severity is variable. Confirmation of genotype in the affected grandsons of this pedigree in principle may enable them to avail of upcoming gene therapies, provided there is anatomical evidence (from multimodal imaging) of potentially reversible early stage disease.
| S-EPMC6233547 | biostudies-literature
Project description:PurposeTo evaluate macular cone structure in patients with X-linked retinoschisis (XLRS) caused by mutations in exon 6 of the RS1 gene.MethodsHigh-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) in two patients with XLRS and 27 age-similar healthy subjects. Retinal structure was correlated with best-corrected visual acuity, kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The six coding exons and the flanking intronic regions of the RS1 gene were sequenced in each patient.ResultsTwo unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic ERG b-wave was reduced more than the a-wave. SD-OCT showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. In each patient, a mutation in exon 6 of the RS1 gene was identified and was predicted to change the amino acid sequence in the discoidin domain of the retinoschisin protein.ConclusionsAOSLO images of two patients with molecularly characterized XLRS revealed increased cone spacing and abnormal packing in the macula of each patient, but cone coverage and function were near normal outside the central foveal schisis cavities. Although cone density is reduced, the preservation of wave-guiding cones at the fovea and eccentric macular regions has prognostic and therapeutic implications for XLRS patients with foveal schisis. (Clinical Trials.gov number, NCT00254605.).
| S-EPMC3341122 | biostudies-literature
Project description:ObjectiveTo evaluate efficacy of a novel adeno-associated virus (AAV) vector, AAV2/4-RS1, for retinal rescue in the retinoschisin knockout (Rs1-KO) mouse model of X-linked retinoschisis (XLRS). Brinzolamide (Azopt®), a carbonic anhydrase inhibitor, was tested for its ability to potentiate the effects of AAV2/4-RS1.MethodsAAV2/4-RS1 with a cytomegalovirus (CMV) promoter (2x1012 viral genomes/mL) was delivered to Rs1-KO mice via intravitreal (N = 5; 1μL) or subretinal (N = 21; 2μL) injections at postnatal day 60-90. Eleven mice treated with subretinal therapy also received topical Azopt® twice a day. Serial full field electroretinography (ERG) was performed starting at day 50-60 post-injection. Mice were evaluated using a visually guided swim assay (VGSA) in light and dark conditions. The experimental groups were compared to untreated Rs1-KO (N = 11), wild-type (N = 12), and Rs1-KO mice receiving only Azopt® (N = 5). Immunofluorescence staining was performed to assess RS1 protein expression following treatment.ResultsThe ERG b/a ratio was significantly higher in the subretinal plus Azopt® (p<0.0001), subretinal without Azopt® (p = 0.0002), and intravitreal (p = 0.01) treated eyes compared to untreated eyes. There was a highly significant subretinal treatment effect on ERG amplitudes collectively at 7-9 months post-injection (p = 0.0003). Cones showed more effect than rods. The subretinal group showed improved time to platform in the dark VGSA compared to untreated mice (p<0.0001). RS1 protein expression was detected in the outer retina in subretinal treated mice and in the inner retina in intravitreal treated mice.ConclusionsAAV2/4-RS1 shows promise for improving retinal phenotype in the Rs1-KO mouse model. Subretinal delivery was superior to intravitreal. Topical brinzolamide did not improve efficacy. AAV2/4-RS1 may be considered as a potential treatment for XLRS patients.
| S-EPMC9728878 | biostudies-literature
Project description:This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c+ myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123+ plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11b+CD11c+ DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9-3e11 vector genomes [vg]/eye). CD8+human leukocyte antigen-DR isotype (HLA-DR)+ cytotoxic T cells and CD68+CD80+ macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines.
| S-EPMC8178519 | biostudies-literature