scholarly journals SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization

2020 ◽  
Vol 29 (18) ◽  
pp. 2989-3002 ◽  
Author(s):  
Helen J Kuht ◽  
Jinu Han ◽  
Gail D E Maconachie ◽  
Sung Eun Park ◽  
Seung-Tae Lee ◽  
...  
Keyword(s):  
Outer Segment ◽  
Transmembrane Domain ◽  
Retinal Development ◽  
Anterior Segment ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment ◽  
Multi Centre Study ◽  
Photoreceptor Layer ◽  
Foveal Hypoplasia

Abstract Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.

scholarly journals Loss of CEP162 function at the primary cilium delays ciliogenesis and causes retinal ciliopathy in humans

2021 ◽  
Author(s):  
Nafisa Nuzhat ◽  
Kristof Van Schil ◽  
Sandra Liakopoulos ◽  
Miriam Bauwens ◽  
Alfredo Dueñas Rey ◽  
...  
Keyword(s):  
Transition Zone ◽  
Primary Cilium ◽  
Outer Segment ◽  
Retinal Dystrophy ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Photoreceptor Outer Segment ◽  
Zone Formation ◽  
Mother Centriole

Ciliopathies often comprise retinal degeneration since the photoreceptor outer segment is an adapted primary cilium. CEP162 is a distal end centriolar protein required for proper transition zone assembly during ciliogenesis and whose loss causes ciliopathy in zebrafish. CEP162 has so far not been implicated in human disease. Here, we identified a homozygous CEP162 frameshift variant, c.1935dupA (p.(E646R*5)), in retinitis pigmentosa patients from two unrelated Moroccan families, likely representing a founder allele. We found that even though mRNA levels were reduced, the truncated CEP162-E646R*5 protein was expressed and localized to the mitotic spindle during mitosis, but not at the basal body of the cilium. In CEP162 knockdown cells, expression of the truncated CEP162-E646R*5 protein is unable to restore ciliation indicating its loss of function at the cilium. In patient fibroblasts, cilia overcome the absence of CEP162 from the primary cilium by delaying ciliogenesis through the persistence of CP110 at the mother centriole. The patient fibroblasts are ultimately able to extend some abnormally long cilia that are missing key transition zone components. Defective transition zone formation likely disproportionately affects the long-living ciliary outer segment of photoreceptors resulting in retinal dystrophy. CEP162 is expressed in human retina, and we show that wild-type CEP162, but not truncated CEP162-E646R*5, specifically localizes to the distal end of centrioles of mouse photoreceptor cilia. Together, our genetic, cell-based, and in vivo modeling establish that CEP162 deficiency causes retinal ciliopathy in humans.

scholarly journals Acute Zonal Cone Photoreceptor Outer Segment Loss

2017 ◽  
Vol 135 (5) ◽  
pp. 487 ◽  
Author(s):  
Tomas S. Aleman ◽  
Harpal S. Sandhu ◽  
Leona W. Serrano ◽  
Anastasia Traband ◽  
Marisa K. Lau ◽  
...  
Keyword(s):  
Outer Segment ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment

Early cone photoreceptor outer segment length shortening in RPGR X-linked retinitis pigmentosa

2020 ◽  
Author(s):  
Moreno Menghini ◽  
Jasleen K. Jolly ◽  
Anika Nanda ◽  
Laura Wood ◽  
Jasmina Cehajic-Kapetanovic ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Outer Segment ◽  
Segment Length ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment

scholarly journals The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival

2017 ◽  
Vol 58 (1) ◽  
pp. 448 ◽  
Author(s):  
Emma M. Lessieur ◽  
Joseph Fogerty ◽  
Robert J. Gaivin ◽  
Ping Song ◽  
Brian D. Perkins
Keyword(s):  
Outer Segment ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment

scholarly journals Rim formation is not a prerequisite for distribution of cone photoreceptor outer segment proteins

2014 ◽  
Vol 28 (8) ◽  
pp. 3468-3479 ◽  
Author(s):  
Shannon M. Conley ◽  
Muayyad R. Al‐Ubaidi ◽  
Zongchao Han ◽  
Muna I. Naash
Keyword(s):  
Outer Segment ◽  
Cone Photoreceptor ◽  
Photoreceptor Outer Segment

scholarly journals Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract–induced Retinal Degeneration in F344/N Rats

2018 ◽  
Vol 46 (5) ◽  
pp. 564-573 ◽  
Author(s):  
Haruhiro Yamashita ◽  
Mark J. Hoenerhoff ◽  
Keith R. Shockley ◽  
Shyamal D. Peddada ◽  
Kevin E. Gerrish ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Morphological Alteration ◽  
Albino Rats ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Layer ◽  
Epithelial Homeostasis ◽  
Kava Kava

There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.

Systematic in-vivo investigation of intrinsic optical signals in the photoreceptor outer segment (Conference Presentation)

2018 ◽  
Author(s):  
Clara Pfäffle ◽  
Dierck Hillmann ◽  
Hendrik Spahr ◽  
Bastian Kabuth ◽  
Gereon M. Hüttmann
Keyword(s):  
Outer Segment ◽  
Photoreceptor Outer Segment ◽  
Optical Signals

scholarly journals Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain

2021 ◽  
Vol 22 (15) ◽  
pp. 7918
Author(s):  
Jisun Hwang ◽  
Bohee Jang ◽  
Ayoung Kim ◽  
Yejin Lee ◽  
Joonha Lee ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Cytoplasmic Domain ◽  
Nih3t3 Cells ◽  
C Elegans ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Signaling Events

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

scholarly journals Chemically-Boosted Corneal Cross-Linking for the Treatment of Keratoconus through a Riboflavin 0.25% Optimized Solution with High Superoxide Anion Release

2021 ◽  
Vol 10 (6) ◽  
pp. 1324
Author(s):  
Cosimo Mazzotta ◽  
Marco Ferrise ◽  
Guido Gabriele ◽  
Paolo Gennaro ◽  
Alessandro Meduri
Keyword(s):  
Superoxide Anion ◽  
Hydroxypropyl Methylcellulose ◽  
Anterior Segment ◽  
Preclinical Study ◽  
Cross Linking ◽  
Specular Microscopy ◽  
The Novel ◽  
Power Setting ◽  
Contralateral Eye

The purpose of this study was to evaluate the effectiveness and safety of a novel buffered riboflavin solution approved for corneal cross-linking (CXL) in progressive keratoconus and secondary corneal ectasia. Following the in vivo preclinical study performed on New Zealand rabbits comparing the novel 0.25% riboflavin solution (Safecross®) containing 1% hydroxypropyl methylcellulose (HPMC) with a 0.25% riboflavin solution containing 0.10% EDTA, accelerated epithelium-off CXL was performed on 10 patients (10 eyes treated, with the contralateral eye used as control) through UV-A at a power setting of 9 mW/cm2 with a total dose of 5.4 J/cm2. Re-epithelialization was evaluated in the postoperative 7 days by fluorescein dye test at biomicroscopy; endothelial cell count and morphology (ECD) were analyzed by specular microscopy at the 1st and 6th month of follow-up and demarcation line depth (DLD) measured by anterior segment optical coherence tomography (AS-OCT) one month after the treatment. We observed complete re-epithelization in all eyes between 72 and 96 h after surgery (88 h on average). ECD and morphology remained unchanged in all eyes. DLD was detected at a mean depth of 362 ± 50 µm, 20% over solutions with equivalent dosage. SafeCross® riboflavin solution chemically-boosted corneal cross-linking seems to optimize CXL oxidative reaction by higher superoxide anion release, improving DLD by a factor of 20%, without adverse events for corneal endothelium.

scholarly journals Macular Pigment Optical Density and Photoreceptor Outer Segment Length as Predisease Biomarkers for Age-Related Macular Degeneration

2020 ◽  
Vol 9 (5) ◽  
pp. 1347 ◽  
Author(s):  
Norihiro Nagai ◽  
Sakiko Minami ◽  
Misa Suzuki ◽  
Hajime Shinoda ◽  
Toshihide Kurihara ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Optical Density ◽  
Outer Segment ◽  
Macular Pigment ◽  
Age Related Macular Degeneration ◽  
Segment Length ◽  
Macular Pigment Optical Density ◽  
Photoreceptor Outer Segment ◽  
Age Related ◽  
Fellow Eyes

To explore predisease biomarkers, which may help screen for the risk of age-related macular degeneration (AMD) at very early stages, macular pigment optical density (MPOD) and photoreceptor outer segment (PROS) length were analyzed. Thirty late AMD fellow eyes, which are at high risk and represent the predisease condition of AMD, were evaluated and compared with 30 age-matched control eyes without retinal diseases; there was no early AMD involvement in the AMD fellow eyes. MPOD was measured using MPS2® (M.E. Technica Co. Ltd., Tokyo, Japan), and PROS length was measured based on optical coherence tomography images. MPOD levels and PROS length in the AMD fellow eyes were significantly lower and shorter, respectively, than in control eyes. MPOD and PROS length were positively correlated in control eyes (R = 0.386; p = 0.035) but not in AMD fellow eyes. Twenty (67%) AMD fellow eyes met the criteria of MPOD < 0.65 and/or PROS length < 35 μm, while only five (17%) control eyes did. After adjusting for age and sex, AMD fellow eyes more frequently satisfied the definition (p < 0.001; 95% confidence interval, 3.50–60.4; odds ratio, 14.6). The combination of MPOD and PROS length may be a useful biomarker for screening predisease AMD patients, although further studies are required in this regard.

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