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1.
Int J Mol Sci ; 25(15)2024 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-39125773

RESUMEN

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.


Asunto(s)
Proteínas del Ojo , Células Madre Pluripotentes Inducidas , Organoides , Retina , Retinosquisis , Humanos , Retinosquisis/genética , Retinosquisis/metabolismo , Retinosquisis/patología , Organoides/metabolismo , Organoides/patología , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Retina/metabolismo , Retina/patología , Diferenciación Celular/genética , Modelos Biológicos
2.
BMJ Open Ophthalmol ; 9(1)2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39209741

RESUMEN

AIMS: To assess peripapillary retinal nerve fibre layer (pRNFL) thickness in patients with X-linked retinoschisis (XLRS), as pRNFL thinning may limit functional improvements in gene therapy trials. METHODS: This retrospective multicentre study included 49 eyes from 25 patients diagnosed with XLRS. Data collected with multimodal imaging at baseline and last follow-up (when available) included age, best-recorded visual acuity (BRVA), central retinal thickness, macular volume (MV), presence and location of peripheral retinoschisis and pRNFL thickness in the global (G), superotemporal (TS), superonasal (NS), inferotemporal (TI), inferonasal (NI), nasal (N) and temporal (T) sectors. Retinal sensitivity, assessed by microperimetry, was also recorded for seven patients at baseline. RESULTS: pRNFL was thinner (below the fifth percentile) in at least one sector in 72% of right eyes and 79% of left eyes, with thinning across three or more sectors in 20% of right and 17% of left eyes. In 44% of cases, thinning occurred in the temporal sectors of both eyes, with no nasal sectoral thinning. Number of peripheral retinoschisis quadrants matched thinned pRNFL sectors. A strong positive correlation was found between MV and temporal pRNFL thickness (r=0.71, p<0.01), while weak negative correlation trends were noted with age (p=0.05) and BRVA (logMAR; p=0.12) related to temporal thickness of pRNFL sectors. CONCLUSION: pRNFL thinning, predominantly sectoral and linked to macular or peripheral retinoschisis, occurs in about three-quarters of patients with XLRS, while diffuse thinning occurs in one-fifth. Temporal pRNFL thinning might occur only after the collapse of intraretinal cystoid cavities in the macula.


Asunto(s)
Fibras Nerviosas , Células Ganglionares de la Retina , Retinosquisis , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Retinosquisis/patología , Retinosquisis/diagnóstico por imagen , Retinosquisis/fisiopatología , Retinosquisis/genética , Estudios Retrospectivos , Masculino , Adulto , Agudeza Visual/fisiología , Fibras Nerviosas/patología , Adolescente , Niño , Adulto Joven , Persona de Mediana Edad , Células Ganglionares de la Retina/patología , Femenino , Campos Visuales/fisiología , Disco Óptico/patología , Disco Óptico/diagnóstico por imagen , Pruebas del Campo Visual , Estudios de Seguimiento
3.
Stem Cell Res Ther ; 15(1): 152, 2024 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-38816767

RESUMEN

BACKGROUND: X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS. METHODS: hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy. RESULTS: ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation. CONCLUSIONS: The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.


Asunto(s)
Proteínas del Ojo , Terapia Genética , Organoides , Retina , Retinosquisis , Humanos , Masculino , Diferenciación Celular , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Terapia Genética/métodos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Organoides/metabolismo , Retina/metabolismo , Retina/patología , Retinosquisis/genética , Retinosquisis/terapia , Retinosquisis/patología , Retinosquisis/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología
4.
Br J Ophthalmol ; 108(11): 1564-1570, 2024 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-38811052

RESUMEN

AIMS: Choroidal neovascularisation (CNV) in patients with X-linked retinoschisis (XLRS) has been poorly documented. This study aims to investigate the prevalence and clinical characteristics of CNV in patients with XLRS, as well as analyse the preliminary genotype-phenotype correlation. METHODS: A retrospective case series of patients with genetically confirmed XLRS was included. Demographic, clinical and genetic features were analysed, with a comparison between CNV and non-CNV eyes. RESULTS: Among 185 eyes of 129 patients with XLRS, the prevalence of CNV was 8.1% (15/185). The mean diagnostic age of all patients with CNV is 5.1±2.56 years. CNV eyes exhibited a mean best-corrected visual acuity (BCVA) (logarithm of the minimal angle of resolution) of 1.37±0.74. All CNVs were classified as subretinal and active. Peripapillary CNVs accounted for 80.0% (12/15), while subfoveal CNVs accounted for 20.0% (3/15). In CNV eyes, the prevalence of macular atrophy (5/15, 33.3%, p=0.013) and bullous peripheral schisis (14/15, 93.3%, p=0.000) was higher compared with non-CNV eyes. Additionally, CNV eyes exhibited poorer integrity of the outer retina and BCVA (p=0.007) compared with non-CNV eyes. All 15 eyes with CNV underwent anti-vascular endothelial growth factor (anti-VEGF) therapy. Genotype analysis revealed that 7 of 10 patients (70.0%, 10 eyes) were predicted to have missense variants, while 3 of 10 patients (30.0%, 5 eyes) exhibited severe variants. CONCLUSIONS: The prevalence of CNV in XLRS eyes was found to be 8.1%. All CNVs secondary to XLRS were active and classified as type 2. CNV eyes demonstrated poorer visual function and compromised retinal structures. Anti-VEGF therapy demonstrated effectiveness in treating XLRS-CNVs. No significant genotype-phenotype correlation was established.


Asunto(s)
Neovascularización Coroidal , Angiografía con Fluoresceína , Retinosquisis , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Retinosquisis/genética , Retinosquisis/diagnóstico , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/genética , Masculino , Estudios Retrospectivos , Agudeza Visual/fisiología , Niño , Femenino , Preescolar , Adolescente , Prevalencia , Estudios de Asociación Genética , Adulto , Proteínas del Ojo/genética , Inhibidores de la Angiogénesis/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/genética , Lactante
5.
Hum Gene Ther ; 35(9-10): 342-354, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38661546

RESUMEN

X-linked retinoschisis (XLRS) is a monogenic recessive inherited retinal disease caused by defects in retinoschisin (RS1). It manifests clinically as retinal schisis cavities and a disproportionate reduction of b-wave amplitude compared with the a-wave amplitude. Currently there is no approved treatment. In the last decade, there has been major progress in the development of gene therapy for XLRS. Previous preclinical studies have demonstrated the treatment benefits of hRS1 gene augmentation therapy in mouse models. However, outcomes in clinical trials have been disappointing, and this might be attributed to dysfunctional assembly of RS1 complexes and/or the impaired targeted cells. In this study, the human synapsin 1 gene promoter (hSyn) was used to control the expression of hRS1 to specifically target retinal ganglion cells and our results confirmed the specific expression and functional assembly of the protein. Moreover, our results demonstrated that a single intravitreal injection of rAAV2-hSyn-hRS1 results in architectural restoration of retinal schisis cavities and improvement in vision in a mouse model of XLRS. In brief, this study not only supports the clinical development of the rAAV2-hSyn-hRS1 vector in XLRS patients but also confirms the therapeutic potential of rAAV-based gene therapy in inherited retinal diseases.


Asunto(s)
Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Vectores Genéticos , Inyecciones Intravítreas , Ratones Noqueados , Células Ganglionares de la Retina , Retinosquisis , Sinapsinas , Animales , Dependovirus/genética , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Ratones , Terapia Genética/métodos , Retinosquisis/terapia , Retinosquisis/genética , Humanos , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Sinapsinas/genética , Sinapsinas/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Expresión Génica , Regiones Promotoras Genéticas , Retina/metabolismo , Retina/patología , Técnicas de Transferencia de Gen
6.
Exp Eye Res ; 242: 109872, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38514024

RESUMEN

X-linked retinoschisis (XLRS) is an early onset degenerative retinal disease characterized by cystic lesions in the middle layers of the retina. These structural changes are accompanied by a loss of visual acuity and decreased contrast sensitivity. XLRS is caused by mutations in the gene Rs1 which encodes the secreted protein Retinoschisin 1. Young Rs1-mutant mouse models develop key hallmarks of XLRS including intraretinal schisis and abnormal electroretinograms. The electroretinogram (ERG) comprises activity of multiple cellular generators, and it is not known how and when each of these is impacted in Rs1 mutant mice. Here we use an ex vivo ERG system and pharmacological blockade to determine how ERG components generated by photoreceptors, ON-bipolar, and Müller glial cells are impacted in Rs1 mutants and to determine the time course of these changes. We report that ERG abnormalities begin near eye-opening and that all ERG components are involved.


Asunto(s)
Moléculas de Adhesión Celular , Modelos Animales de Enfermedad , Electrorretinografía , Proteínas del Ojo , Retinosquisis , Animales , Retinosquisis/genética , Retinosquisis/fisiopatología , Ratones , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Ratones Endogámicos C57BL , Mutación , Células Ependimogliales/patología , Células Ependimogliales/metabolismo , Masculino , Células Bipolares de la Retina/patología , Células Bipolares de la Retina/metabolismo
7.
Indian J Ophthalmol ; 72(6): 902-911, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38317323

RESUMEN

PURPOSE: Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X-linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations. METHODS: A total of 22 probands were suspected of having X-linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 in silico tools. RESULTS: The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel-like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b-wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene's signal sequence. CONCLUSION: This study provides valuable insights into the spectrum of RS1 mutations in X-linked retinoschisis probands from South India. It reveals distinct genotypic-phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis.


Asunto(s)
Proteínas del Ojo , Genotipo , Mutación , Fenotipo , Retinosquisis , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , ADN/genética , Análisis Mutacional de ADN , Electrorretinografía , Proteínas del Ojo/genética , India , Linaje , Retina/diagnóstico por imagen , Retina/patología , Retinosquisis/diagnóstico , Retinosquisis/genética , Retinosquisis/patología , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología
8.
Int J Mol Sci ; 25(2)2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38279267

RESUMEN

X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (RS1, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I2). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine RS1 in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.


Asunto(s)
Retinosquisis , Masculino , Humanos , Animales , Ratones , Retinosquisis/genética , Retinosquisis/terapia , Retinosquisis/diagnóstico , Retina/patología , Electrorretinografía , Terapia Genética , Mutación , Proteínas del Ojo/genética
9.
Doc Ophthalmol ; 148(1): 65-71, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38172268

RESUMEN

PURPOSE: In this study, we report a case of a young adult with X-linked juvenile retinoschisis (XLRS) with a rare pathogenic variant in the RS1 gene (c.522 + 2 T > A). METHODS: Ophthalmological evaluation, optical coherence tomography, full-field and multifocal electroretinograms and extensive genetic screening of genes related to visual loss were carried out in the participant. RESULTS: Clinical ophthalmological exams revealed a mild to moderate impairment of visual acuity. Retinal imaging showed bilateral foveal schisis, as well as normal a-wave, reduction in the b-wave amplitudes in dark- and light- adapted full-field electroretinograms, and abnormal oscillatory potentials. We found also diffuse amplitude reduction in multifocal electroretinogram arrays. A canonical splice variant was identified in the RS1 gene (c.522 + 2 T > A). CONCLUSION: A rare pathogenic variant of the RS1 gene was associated with diffuse retinal involvement (central and peripheral retina), probably in inner retina, and mild to moderate visual acuity impairment. The phenotypical characterization of rare mutations is relevant to provide information about the disease.


Asunto(s)
Electrorretinografía , Retinosquisis , Adulto Joven , Humanos , Retina/patología , Retinosquisis/diagnóstico , Retinosquisis/genética , Mutación , Fóvea Central/patología , Proteínas del Ojo/genética , Tomografía de Coherencia Óptica
10.
JAMA Ophthalmol ; 142(2): 158-161, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38153728

RESUMEN

This case report describes 2 individuals with hyperreflective columns in the outer nuclear layer observed on optical coherence tomography and possible implications for CRB1-associated maculopathy.


Asunto(s)
Degeneración Macular , Enfermedades de la Retina , Retinosquisis , Humanos , Retinosquisis/diagnóstico por imagen , Retinosquisis/genética , Tomografía de Coherencia Óptica/métodos , Fóvea Central , Proteínas del Ojo/genética , Proteínas de la Membrana , Proteínas del Tejido Nervioso
11.
Stem Cell Res ; 73: 103263, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38011758

RESUMEN

X-linked retinoschisis (XLRS) is one of the most common retinal genetic diseases with progressive visual impairment in childhood affecting males. It is manifested with macular and/or peripheral schisis in neural retinas with no effective treatment. Previously, we successfully generated a human-induced pluripotent stem cell (iPSC) line from an XLRS patient carrying the hemizygous RS1 c. 304C > T (p.R102W) mutation. Here, we corrected the c.304C > T mutation in the RS1 gene using CRISPR/Cas9 technology to generate an isogenic control. This cell line is valuable for the study of XLRS.


Asunto(s)
Células Madre Pluripotentes Inducidas , Retinosquisis , Masculino , Humanos , Retinosquisis/genética , Retinosquisis/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Retina/metabolismo , Línea Celular , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo
13.
Exp Eye Res ; 234: 109591, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37481224

RESUMEN

X-linked juvenile retinoschisis (XLRS), a hereditary retinal disorder primarily affecting males, is characterized by the formation of cystic spaces between the outer plexiform layer and outer nuclear layer of the retina. Mutations in the RS1 gene, which encodes the extracellular binding protein retinoschisin, are responsible for XLRS pathogenesis. While the role of retinoschisin in maintaining retinal integrity is well established, there is growing evidence suggesting compromised photoreceptor function in XLRS. To investigate the molecular pathways affected by RS1 deficiency, particularly in phototransduction, we performed electroretinographic (ERG) and proteomic analyses on retinae from Rs1 knockout mice, a model of human XLRS. The Rs1 knockout mice had reduced ERG a-wave amplitudes. Correspondingly, differential expression analysis revealed downregulation of proteins crucial for phototransduction, with Ingenuity Pathway Analysis (IPA) highlighting "phototransduction" as the most significantly downregulated biological theme. Compensatory mechanisms were also observed in the IPA, including upregulation of synaptic remodeling, inflammation, cell adhesion, and G-protein signaling. These findings strongly implicate an underrecognized role of photoreceptor dysfunction in XLRS pathology. We speculate that entrapment of mutant retinoschisin protein within photoreceptor inner segments as well as disrupted reciprocal regulation between L-type voltage-gated calcium channels and retinoschisin contribute to the dysfunction in photoreceptors.


Asunto(s)
Retinosquisis , Humanos , Masculino , Animales , Ratones , Retinosquisis/genética , Proteómica , Moléculas de Adhesión Celular/genética , Retina/metabolismo , Ratones Noqueados , Proteínas del Ojo/metabolismo
14.
Genes (Basel) ; 14(6)2023 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-37372373

RESUMEN

X-linked retinoschisis (XLRS) is the most common juvenile macular degeneration in males. Unlike most other X-linked retinal dystrophies, carrier heterozygous females are very rarely reported to show clinical features of the disease. Herein, we describe unusual retinal features in a 2-year-old female infant with family history and genetic testing consistent with XLRS.


Asunto(s)
Retinosquisis , Femenino , Humanos , Proteínas del Ojo/genética , Fenotipo , Retina/patología , Retinosquisis/genética , Retinosquisis/patología , Inactivación del Cromosoma X/genética , Preescolar
15.
Am J Med Genet A ; 191(10): 2524-2535, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37317958

RESUMEN

X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.


Asunto(s)
Retinosquisis , Preescolar , Masculino , Humanos , Retinosquisis/diagnóstico , Retinosquisis/genética , Retinosquisis/metabolismo , Mutación Missense/genética , Retina/patología , Pliegue de Proteína , India , Proteínas del Ojo/genética
16.
J AAPOS ; 27(3): 174-176, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37196916

RESUMEN

Juvenile X-linked retinoschisis (JXR), the most common inherited retinal disorder in young males, presents with a wide range of phenotypic variations. Acute angle closure in children with JXR has been reported in the literature only once before. We present a case of acute-angle closure, temporally associated with pharmacologic dilation, in a 12-year-old boy with JXR.


Asunto(s)
Oftalmopatías , Enfermedades de la Retina , Retinosquisis , Masculino , Niño , Humanos , Retinosquisis/diagnóstico , Retinosquisis/genética , Enfermedad Aguda , Retina
17.
BMC Ophthalmol ; 23(1): 159, 2023 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-37069516

RESUMEN

BACKGROUND: X-linked retinoschisis (XLRS), due to mutations in the RS1 gene, is a common genetically determined form of macular degeneration. This report describes an unusual case of angle-closure glaucoma (ACG) with XLRS and discusses the treatment. CASE PRESENTATION: A 39-year-old Chinese man with an X chromosome-recessive inherited c.489G > A variant in the RS1 gene was diagnosed as XLRS and ACG, presenting with cystic macular lesions, shallow anterior chamber depth (ACD), and angle-closure with uncontrolled intraocular pressure (IOP). Malignant glaucoma occurred following trabeculectomy combining phacoemulsification with intraocular lens (IOL) implantation and goniosynechialysis. Subsequent anterior vitrectomy and irido-zonulo-hyaloid-vitrectomy (IZHV) effectively lowered IOP and deepened ACD, but the cystic cavity became larger. CONCLUSIONS: There is a potential risk of malignant glaucoma in ACG patients with XLRS after filtering surgery. Although anterior vitrectomy can effectively resolve aqueous misdirection, the macular retinoschisis may get worse. Awareness of this risk may aid in surgical planning and postoperative management in these patients.


Asunto(s)
Extracción de Catarata , Glaucoma de Ángulo Cerrado , Glaucoma , Facoemulsificación , Retinosquisis , Masculino , Humanos , Adulto , Glaucoma de Ángulo Cerrado/complicaciones , Glaucoma de Ángulo Cerrado/genética , Glaucoma de Ángulo Cerrado/cirugía , Retinosquisis/diagnóstico , Retinosquisis/genética , Retinosquisis/cirugía , Implantación de Lentes Intraoculares/efectos adversos , Glaucoma/cirugía , Presión Intraocular
18.
Ophthalmic Genet ; 44(3): 262-270, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36856325

RESUMEN

PURPOSE: X-linked juvenile retinoschisis (XLRS) is the most common congenital retinoschisis in rare vitreoretinopathy and causes visual disturbances. The study aimed to explore possible genetic mutations associated with XLRS and assess the clinical characteristics in Chinese families. METHODS: Seventeen cases and thirty-four eyes of probands and thirty-nine cases and seventy-eight eyes of their guardians were recruited. Peripheral blood DNA was extracted and PCR-amplified for retinal disease second-generation panel sequencing to screen for mutated genes. Pathogenicity was referred to the guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: A total of 17 male patients were included, with an average age of 9.73 years (range, 5 ~ 27 years). Clinical data indicate typical macular retinoschisis (97.06%), peripheral retinoschisis (46.67%), retinal holes (32.35%). Fifteen mutations (10 missense mutations, 4 shift mutations, and 3 nonsense mutations) of RS1 gene were identified, including 5 novel mutations. In novel mutations, amino acid conservation analysis shows W33, W50, E62, and G70 were highly conserved, and software predicts mutations to be pathogenic. SWISS-MODEL protein prediction software showed protein structural changes in proband 13. CONCLUSIONS: We have identified and described five novel mutations in the RS1 gene and their corresponding clinical manifestations. These findings not only expand the range of known RS1 mutations and associated clinical phenotypes but also provide a basis for mechanistic studies and diagnosis of XLRS.


Asunto(s)
Retinosquisis , Masculino , Humanos , Retinosquisis/diagnóstico , Retinosquisis/genética , Retinosquisis/patología , Análisis Mutacional de ADN , Mutación , Mutación Missense , Codón sin Sentido , Proteínas del Ojo/genética , Electrorretinografía
19.
Ophthalmic Genet ; 44(6): 610-617, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36927170

RESUMEN

BACKGROUND: X-linked retinoschisis (XLRS) is a rare inherited bilateral retinal degeneration caused by mutations in RS1 gene, occurring exclusively in men. Various ocular complications associated with XLRS are reported, and angle closure glaucoma in these eyes is one such complication that is refractory and needs surgery for intraocular pressure control. Glaucoma surgery in these eyes often results in refractory malignant glaucoma with its serious sequelae. Several surgical modifications to prevent this complication have been tried with no or limited success. METHODOLOGY: In this report, we present a case of XLRS in a young male with a 22-year follow-up. We have described the natural history and progression of retinal disease and glaucoma. RESULTS: Refractory angle closure glaucoma in our patient was treated with core vitrectomy, phacoemulsification with intraocular lens implantation, and irido-zonulo-hyaloido-vitrectomy. This helped in successful deepening of anterior chamber, good IOP control, and preventing malignant glaucoma. CONCLUSION: Our case highlights the role of vitrectomy in managing the secondary angle closure glaucoma in eyes with X-LRS.


Asunto(s)
Glaucoma de Ángulo Cerrado , Glaucoma , Retinosquisis , Humanos , Masculino , Glaucoma de Ángulo Cerrado/genética , Glaucoma de Ángulo Cerrado/cirugía , Retinosquisis/genética , Retinosquisis/cirugía , Glaucoma/patología , Cámara Anterior/patología , Presión Intraocular
20.
Artículo en Inglés | MEDLINE | ID: mdl-36690462

RESUMEN

X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas in 1898 and is clinically diagnosed by characteristic intraretinal cysts arranged in a petaloid "spoke-wheel" pattern centered in the macula. When clinical electroretinogram (ERG) testing began in the 1960s, XLRS was noted to have a characteristic reduction of the dark-adapted b-wave amplitude despite normal or usually nearly normal a-wave amplitudes, which became known as the "electronegative ERG response" of XLRS disease. The causative gene, RS1, was identified on the X-chromosome in 1997 and led to understanding the molecular and cellular basis of the condition, discerning the structure and function of the retinoschisin protein, and generating XLRS murine models. Along with parallel development of gene delivery vectors suitable for targeting retinal diseases, successful gene augmentation therapy was demonstrated by rescuing the XLRS phenotype in mouse. Two human phase I/II therapeutic XLRS gene augmentation studies were initiated; and although these did not yield definitive improvement in visual function, they gave significant new knowledge and experience, which positions the field for further near-term clinical testing with enhanced, next-generation gene therapy for XLRS patients.


Asunto(s)
Retinosquisis , Masculino , Humanos , Animales , Ratones , Retinosquisis/genética , Retinosquisis/terapia , Retinosquisis/diagnóstico , Mutación , Electrorretinografía , Fenotipo , Terapia Genética , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Retina/metabolismo
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