Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling

Vijayasarathy, Camasamudram; Pasha, Sheik Pran Babu Sardar; Sieving, Paul A.

doi:10.1016/j.preteyeres.2021.100999

Cited by 15 publications

(17 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown no significant association between the RS1 genotype and XLRS phenotype (Hewitt et al, 2005;Pimenides et al, 2005;Riveiro-Alvarez et al, 2009;Bowles et al, 2011;Vincent et al, 2013;Fahim et al, 2017;Hahn Vijayasarathy et al, 2021). It was also proved in this study.…”

Section: Discussionsupporting

confidence: 81%

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Guo

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Purpose: X-linked juvenile retinoschisis (XLRS), caused by mutations in the RS1 gene, is an X-linked recessive inherited disease that typically involves both eyes in the first 2 decades of life. Recently, the phenotype heterogeneity of this condition has drawn increasing attention. We reported various phenotypes caused by RS1 gene mutations in eleven patients from ten Chinese families.Methods: Data on the medical history of the patients from ten Han families of central China were collected. Ophthalmic examinations including best-corrected visual acuity (BCVA), fundus photography, ultra-wide-angle sweep source optical coherence tomography (SS-OCT), and electroretinography (ERG) were performed. Adaptive optics (AO) images were acquired to evaluate the cone photoreceptor mosaic when applicable. Venous blood of the probands and their family members was collected, and DNA was subjected to sequencing based on next-generation sequencing with a custom-designed targeted gene panel PS400 for inherited retinal diseases. Validation was performed by Sanger sequencing and cosegregation. Pathogenicity was determined in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines.Results: Ten RS1 mutations, including eight missense mutations and two terminator mutations, were identified in 10 XLRS families. c.657C > A (p.C219X) was a novel mutation in this cohort. These patients showed a variety of clinical phenotypes, including fovea schisis, bullous retinoschisis, and macular or peripheral atrophy. Fifteen eyes of eight patients exhibited macular retinoschisis, and twelve eyes of seven patients exhibited peripheral retinoschisis. In addition, three patients showed asymmetrical fundus manifestations. Of importance, three patients without macular retinoschisis were misdiagnosed until genetic testing results were obtained. AO showed a decrease in cone density and loss of regularity in the cystic schisis macular of XLRS. Furthermore, the BCVA was associated with the photoreceptor inner segment and outer segment (IS/OS) thickness.Conclusion: With complicated clinical manifestations, a considerable portion of XLRS patients may present various phenotypes. It should be noted that asymmetry in fundus appearance in both eyes could lead to misdiagnosis easily. Thus, genetic testing is crucial for making a final diagnosis in those patients who are suspected of having amblyopia, bilateral or unilateral macular atrophy, or conditions presenting an asymmetric fundus appearance. In addition, the residual cone photoreceptor structure was critical for the maintenance of useful vision.

show abstract

Section: Discussionsupporting

confidence: 81%

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Guo

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

show abstract

“…Genetically engineered XLRS rodent models ( Rs1 gene knockout) recapitulate aspects of schisis pathology observed in the human disease and are critical for understanding disease pathogenesis. 6 These models supported preclinical studies for rAAV8 RS1 gene transfer into XLRS mouse retina ( Fig. 1 C).…”

supporting

confidence: 61%

“… 3 – 5 The clinical pathology, molecular and cell biology of XLRS and the strategies to treat XLRS have been reviewed comprehensively elsewhere. 6 – 11 …”

mentioning

confidence: 99%

Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors

Vijayasarathy

Zeng

Marangoni

et al. 2022

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Purpose Loss of retinoschisin (RS1) function underlies X-linked retinoschisis (XLRS) pathology. In the retina, both photoreceptor inner segments and bipolar cells express RS1. However, the loss of RS1 function causes schisis primarily in the inner retina. To understand these cell type–specific phenotypes, we decoupled RS1 effects in bipolar cells from that in photoreceptors. Methods Bipolar cell transgene RS1 expression was achieved using two inner retina–specific promoters: (1) a minimal promoter engineered from glutamate receptor, metabotropic glutamate receptor 6 gene (mini-mGluR6/ Grm6) and (2) MiniPromoter (Ple155). Adeno-associated virus vectors encoding RS1 gene under either the mini-mGluR6 or Ple-155 promoter were delivered to the XLRS mouse retina through intravitreal or subretinal injection on postnatal day 14. Retinal structure and function were assessed 5 weeks later: immunohistochemistry for morphological characterization, optical coherence tomography and electroretinography (ERG) for structural and functional evaluation. Results Immunohistochemical analysis of RS1expression showed that expression with the MiniPromoter (Ple155) was heavily enriched in bipolar cells. Despite variations in vector penetrance and gene transfer efficiency across the injected retinas, those retinal areas with robust bipolar cell RS1 expression showed tightly packed bipolar cells with fewer cavities and marked improvement in inner retinal structure and synaptic function as judged by optical coherence tomography and electroretinography, respectively. Conclusions These results demonstrate that RS1 gene expression primarily in bipolar cells of the XLRS mouse retina, independent of photoreceptor expression, can ameliorate retinoschisis structural pathology and provide further evidence of RS1 role in cell adhesion.

show abstract

“…Besides, the effect of selective inhibitors on the enzymatic isoforms expressed in the retinal/eye tissues deserves further research. Nevertheless, accelerated shrinkage of the splitting cavity by CAI could be helpful in restoring retinal anatomy, prolong the therapeutic time window for gene therapy, and thereby improve the therapeutic effect ( 45 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Photoreceptor Phenotype Observation and Therapeutic Evaluation of a Carbonic Anhydrase Inhibitor in a X-Linked Retinoschisis Mouse Model

Liu

Wang

et al. 2022

Front. Med.

View full text Add to dashboard Cite

PurposeTo study the long-term photoreceptor changes and to evaluate the effects of topical application of a carbonic anhydrase inhibitor (CAI) in a mouse model of X-linked retinoschisis (XLRS).MethodsConventional electroretinograms (ERGs) and dark-adapted 10-Hz flicker ERGs were recorded in control and Rs1−/Y mice generated with CRISPR/Cas9. ON-pathway blocker 2-amino-4-phosphobutyric acid (APB) was injected intravitreally. Morphology was evaluated with histology and optical coherence tomography (OCT). Mice were treated with a CAI inhibitor brinzolamide eye drops (10 mg/ml) three times a day for 3 months. OCT and ERG findings at 1, 4, and 10 months were analyzed.ResultsNegative ERGs and retinal cavities were evident in Rs1−/Y mice. Both a-wave and b-wave amplitudes decreased with age when compared with age-matched controls. The APB-isolated a-wave (a′) amplitudes of Rs1−/Y mice were reduced in all age groups. In dark-adapted 10-Hz flicker ERG, the amplitude-intensity curve of Rs1−/Y mice shifted down. The thickness of ONL and IS/OS decreased in Rs1−/Y mice. CAI reduced the splitting retinal cavities but didn't affect the ERG.ConclusionsIn addition to post receptoral impairments, photoreceptor cells underwent progressive dysfunction since early age in Rs1−/Y mice. Long-term CAI treatment improved the shrinkage of the splitting retinal cavity, while no functional improvement was observed.

show abstract

Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling

Cited by 15 publications

References 155 publications

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Targeted Expression of Retinoschisin by Retinal Bipolar Cells in XLRS Promotes Resolution of Retinoschisis Cysts Sans RS1 From Photoreceptors

Longitudinal Photoreceptor Phenotype Observation and Therapeutic Evaluation of a Carbonic Anhydrase Inhibitor in a X-Linked Retinoschisis Mouse Model

Contact Info

Product

Resources

About