Molecular Mechanisms Leading to Null-Protein Product from Retinoschisin (RS1) Signal-Sequence Mutants in X-Linked Retinoschisis (XLRS) Disease

Vijayasarathy, Camasamudram; Sui, Ruifang; Zeng, Yong; Yang, Guo‐Yu; Xu, Fei; Caruso, Rafael C.; Lewis, Richard A.; Ziccardi, Lucia; Sieving, Paul A.

doi:10.1002/humu.21350

Cited by 42 publications

(44 citation statements)

References 60 publications

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“…1 The human RS1 gene contains six separate exons that encode a 224-amino-acid cell-surface protein known as retinoschisin (RS1). 2,3 RS1 is highly expressed by the retinal photoreceptor and bipolar cells and interacts with the surfaces of these cells to stabilize the organization of the retina. [4][5][6] Pathogenic mutations of the RS1 gene lead to vitreoretinal dystrophies and progressive deterioration of vision.…”

Section: Introductionmentioning

confidence: 99%

A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family

Huang

Mei

Gui

et al. 2014

Eye

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Purpose X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spokewheel 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. Methods The 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. Results Reduced 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. Conclusions We 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.

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Section: Introductionmentioning

confidence: 99%

A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family

Huang

Mei

Gui

et al. 2014

Eye

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“…Although we have not yet confirmed the phenotype of this variant, M1L is predicted to disrupt mRNA translation, by alteration of the first codon. Similar disruption of codon 1 ( M1V or M1L ) in other genes is associated with a highly penetrant, loss of function phenotype [46-49]. Indeed, the extremely rare M1V variant of CYP2C9 ( CYP2C9*36 ) was recently described in a Chinese population, and its recombinant expression was found to result in low accumulation of the variant enzyme relative to wild-type in COS cells [50].…”

Section: Discussionmentioning

confidence: 99%

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Fohner

Robinson

Yracheta

et al. 2015

Pharmacogenetics and Genomics

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Objectives Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide inter-individual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K dependent blood clotting factors. Methods We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation (SCF) in Anchorage, AK and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific SNPs in larger cohorts of each study population (380 and 350, respectively). Results We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (−1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2 and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Conclusions Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the US, a finding consistent with clinical experience in Alaska.

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“…An N-terminal deletion mutant was also produced (truncated before residue 58). Affinity tags at both ends of the sequence have been shown to yield secreted oligomeric species: an myc tag inserted after the signal sequence (22) and a FLAG tag at the C terminus (23). The C-terminal FLAG tag was shown not to interfere with normal RS1 biological functioning (Fig.…”

Section: Significancementioning

confidence: 99%

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

Tolun

Vijayasarathy

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Retinoschisin (RS1) is involved in cell-cell junctions in the retina, but is unique among known cell-adhesion proteins in that it is a soluble secreted protein. Loss-of-function mutations in RS1 lead to early vision impairment in young males, called X-linked retinoschisis. The disease is characterized by separation of inner retinal layers and disruption of synaptic signaling. Using cryo-electron microscopy, we report the structure at 4.1 Å, revealing double octamer rings not observed before. Each subunit is composed of a discoidin domain and a small N-terminal (RS1) domain. The RS1 domains occupy the centers of the rings, but are not required for ring formation and are less clearly defined, suggesting mobility. We determined the structure of the discoidin rings, consistent with known intramolecular and intermolecular disulfides. The interfaces internal to and between rings feature residues implicated in X-linked retinoschisis, indicating the importance of correct assembly. Based on this structure, we propose that RS1 couples neighboring membranes together through octamer-octamer contacts, perhaps modulated by interactions with other membrane components.retinoschisin | X-linked retinoschisis | discoidin domain | cryo-electron microscopy | single particle analysis T he structural integrity and functioning of tissues are highly dependent on cell-cell junctions. These are typically composed of two similar opposing layers of interacting proteins embedded as oligomers or arrays in the cellular membranes. For example, paired arrays of cadherins are found in adherens junctions and desmosomes (1); of claudins and occludins in tight junctions (2, 3); and of connexin channels in gap junctions (4). The back-to-back architecture of these junctions is fundamental to their adhesive function.The retina features another protein implicated in cell-cell adhesion, retinoschisin (RS1). RS1 is a 24-kDa protein expressed exclusively by photoreceptors and bipolar cells in the retina (5) and pineal gland (6). Loss-of-function mutants of RS1 lead to progressive visual impairment in a disease called X-linked retinoschisis (XLRS) (7-9). The clinical manifestation is a pathological separation of retinal layers, leading to structural splitting and cavity (or "schisis") formation (10). Additionally, the bipolar cells show disorganization (11) and failure to maintain synaptic organization (9). Both XLRS patients and RS1 gene knockout mouse models (Rs1-KO) show similar phenotypes: schisis/splitting through retinal layers and synaptic transmission defects manifested as reduced b-wave amplitudes on the clinical electroretinogram ( Fig. S1) (8, 12). RS1 gene therapy rescues the XLRS mouse phenotype (9, 13) and human RS1 gene therapy trials are underway (ClinicalTrials.gov: NCT02317887; NCT02416622).RS1 is secreted as a soluble disulfide bond-stabilized octamer (14, 15). Most of the monomer comprises a discoidin (DS) domain, a globular fold that is highly conserved over many proteins with diverse functions (16). Little progress has been made toward...

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Molecular Mechanisms Leading to Null-Protein Product from Retinoschisin (RS1) Signal-Sequence Mutants in X-Linked Retinoschisis (XLRS) Disease

Cited by 42 publications

References 60 publications

A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family

A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people

Paired octamer rings of retinoschisin suggest a junctional model for cell–cell adhesion in the retina

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