Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.

Retinoschisis is a poorly documented form of retinal degeneration characterized by cyst-like splitting that occurs between the inner nuclear and outer plexiform layers. The pathogenesis of retinoschisis is incompletely understood, but congenital, acquired and secondary aetiologies (glaucoma, inflammation, neoplasia) are described in humans. This retrospective study investigated the prevalence and associated histological and clinical features of retinoschisis in cats and dogs submitted for biopsy over a 10-year period. Of 140 samples with documented \'retinal vacuolation\', four out of 120 (3%) canine samples and one out of 20 (5%) feline samples had changes consistent with retinoschisis. In most cases (80%), there was concurrent retinal detachment. In cases with available histories, increased intraocular pressure, proptosis and retinal detachment were reported clinical findings. In cats and dogs, retinoschisis is a retinal change that is generally secondary to other ocular lesions.

X-linked retinoschisis (XLRS) shows features also seen in patients with uveitis and is recognized as an uveitis masquerade syndrome. This retrospective study aimed to describe characteristics of XLRS patients with an initial uveitis diagnosis and to contrast these to patients with an initial XLRS diagnosis. Patients referred to a uveitis clinic, which turned out to have XLRS (n = 4), and patients referred to a clinic for inherited retinal diseases (n = 18) were included. All patients underwent comprehensive ophthalmic examinations, including retinal imaging with fundus photography, ultra-widefield fundus imaging, and optical coherence tomography (OCT). In patients with an initial diagnosis of uveitis, a macular cystoid schisis was always interpreted as an inflammatory macular edema; vitreous hemorrhages were commonly interpreted as intraocular inflammation. Patients with an initial diagnosis of XLRS rarely (2/18; p = 0.02) showed vitreous hemorrhages. No additional demographic, anamnestic, and anatomical differences were found. An increased awareness of XLRS as a uveitis masquerade syndrome may facilitate early diagnosis and may prevent unnecessary therapies.

The T-shaped radial spoke (RS) is a protein complex attached to the A microtubule of the outer doublet microtubules, and it extends toward the central pair (CP). It modulates the beat frequency, amplitude, and waveform of the flagella and cilia by serving as a mechanochemical signal transducer between the CP and dyneins. In humans, RS defects cause primary ciliary dyskinesia, but the structural components of triple RSs (RS1, RS2, and RS3) in mammals remain to be elucidated in detail. Here, we introduce a mouse model that lacked the entire RS1 in sperm flagella, due to the deletion of Iqub, while the tracheal cilia possessed intact triple RSs. Furthermore, the absence of IQUB only resulted in male infertility, owing to the sperm motility defect. Based on the mouse model, the RS1 compositions are identified in sperm flagella. In summary, this study elucidates the RS1 components and function in mammalian flagella.

Purpose: We aim to analyze the clinical and genetic features in a Chinese family with congenital retinoschisis by whole-exome sequencing and comprehensive clinical examination. Methods: Six members were recruited from a Chinese family. Three of them were diagnosed as congenital retinoschisis, including two twin siblings. All subjects received a full eye examination. Whole-exome sequencing (WES) and Sanger sequencing were performed on two twin probands and all participants, respectively. Results: A novel splice site mutation RS1.c.53-1G>A was identified in a Chinese congenital retinoschisis family. The mean onset age was 16.7 ± 2.4 years old. The average BCVA in patients was 0.37 ± 0.05. A typical spoke-wheel pattern was observed in all affected eyes. OCT examination results showed fovea schisis and schisis cavities were located in the inner nuclear layer in 100% eyes (6/6). ERG b/a ratio was decreased markedly, but was still more than 1 in the four eyes that were available. Conclusion: The present study discovered a new pathogenic splice cite variant of RS1 in congenital retinoschisis, which expands the mutational spectrum. In contrast to previous research, the phenotype of patients with the same mutation within one family was highly similar. Early molecular testing is crucial for early diagnosis, clinical management, and genetic counseling of patients with congenital retinoschisis.

X-linked retinoschisis (XLRS) is among the most commonly inherited degenerative retinopathies. XLRS is caused by functional impairment of RS1. However, the molecular mechanisms underlying RS1 malfunction remain largely uncharacterized. Here, we performed a data-independent acquisition-mass spectrometry-based proteomic analysis in RS1-null mouse retina with different postal days (Ps), including the onset (P15) and early progression stage (P56). Gene set enrichment analysis showed that type I interferon-mediated signaling was upregulated and photoreceptor proteins responsible for detection of light stimuli were downregulated at P15. Positive regulation of Tor signaling was downregulated and nuclear transcribed mRNA catabolic process nonsense-mediated decay was upregulated at P56. Moreover, the differentially expressed proteins at P15 were enriched in metabolism of RNA and RNA destabilization. A broader subcellular localization distribution and enriched proteins in visual perception and phototransduction were evident at P56. Combined transcriptomic-proteomic analysis revealed that functional impairments, including detection of visible light, visual perception, and visual phototransduction, occurred at P21 and continued until P56. Our work provides insights into the molecular mechanisms underlying the onset and progression of an XLRS mouse model during the early stages, thus enhancing the understanding of the mechanism of XLRS.

The RS1 gene on Xp 22.13 encodes retinoschisin which is known to directly interact with the retinal Na/K-ATPase at the photoreceptor inner segments. Pathologic mutations in RS1 cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy in young males. To further delineate the retinoschisin-Na/K-ATPase complex, co-immunoprecipitation was performed with porcine and murine retinal lysates targeting the ATP1A3 subunit. This identified the voltage-gated potassium (Kv) channel subunits Kv2.1 and Kv8.2 as direct interaction partners of the retinal Na/K-ATPase. Colocalization of the individual components of the complex was demonstrated at the membrane of photoreceptor inner segments. We further show that retinoschisin-deficiency, a frequent consequence of molecular pathology in XLRS, causes mislocalization of the macromolecular complex during postnatal retinal development with a simultaneous reduction of Kv2.1 and Kv8.2 protein expression, while the level of retinal Na/K-ATPase expression remains unaffected. Patch-clamp analysis revealed no effect of retinoschisin-deficiency on Kv channel mediated potassium ion currents in vitro. Together, our data suggest that Kv2.1 and Kv8.2 together with retinoschisin and the retinal Na/K-ATPase are integral parts of a macromolecular complex at the photoreceptor inner segments. Defective compartmentalization of this complex due to retinoschisin-deficiency may be a crucial step in initial XLRS pathogenesis.

UNASSIGNED: To 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).
UNASSIGNED: Conventional 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.
UNASSIGNED: Negative 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.
UNASSIGNED: In 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.

Although it has a poor prognosis, patients with lung adenocarcinoma (LUAD) have a relatively higher 5-year survival period. Thus, it is necessary to identify effective prognostic markers to evaluate the effect of early treatment. RS1 gene encodes retinoschisin, a key protein in congenital retinoschisis, while few studies have been reported on the association between RS1 and cancer prognosis.
We performed bioinformatic analyses based on the data obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases to demonstrate the expression level of RS1 was related to the LUAD prognosis and our findings were verified in-vitro and clinical samples. Then, we explored the potential mechanism of how RS1 expression influenced the prognosis of LUAD.
Compared with normal tissues, the RS1 expression was significantly lower in tumor tissues. The Multivariate Cox regression model showed that RS1 could be used as an independent prognostic indicator. Furthermore, we found significant differences in immune cell infiltration between RS1 high and low expression groups, and the proteasome pathway was found enriched in RS1 low expression samples.
In conclusion, our study suggests that RS1 is a novel prognostic biomarker for LUAD. Differences in immune cell infiltration and signaling pathways may contribute to the poor prognosis of LUAD caused by low RS1 expression.

For disorders with X-linked inheritance, variants may be transmitted through multiple generations of carrier females before an affected male is ascertained. Pathogenic RS1 variants exclusively cause X-linked retinoschisis (XLRS). While RS1 is constrained to variation, recurrent variants are frequently observed in unrelated probands. Here, we investigate recurrent pathogenic variants to determine the relative burden of mutational hotspot and founder allele events to this phenomenon. A cohort RS1 variant analysis and standardized classification, including variant enrichment in the XLRS cohort and in RS1 functional domains, were performed on 332 unrelated XLRS probands. A total of 108 unique RS1 variants were identified. A subset of 19 recurrently observed RS1 variants were evaluated in 190 probands by a haplotype analysis, using microsatellite and single nucleotide polymorphisms. Fourteen variants had at least two probands with common variant-specific haplotypes over ~1.95 centimorgans (cM) flanking RS1. Overall, 99/190 of reportedly unrelated probands had 25 distinct shared haplotypes. Examination of this XLRS cohort for common RS1 haplotypes indicates that the founder effect plays a significant role in this disorder, including variants in mutational hotspots. This improves the accuracy of clinical variant classification and may be generalizable to other X-linked disorders.