Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies DOI Creative Commons
S. Grewal, Joseph J. Smith, Amanda‐Jayne F. Carr

et al.

Therapeutic Advances in Ophthalmology, Journal Year: 2021, Volume and Issue: 13

Published: Jan. 1, 2021

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum disorders is caused by mutations in bestrophin1 (BEST1), protein thought to act as Ca2+-activated Cl- channel pigment epithelium (RPE) eye. Although bestrophinopathies rare, over 250 individual pathological have been identified BEST1 gene, many reported various clinical expressivity and incomplete penetrance. With no current treatments available for patients bestrophinopathies, understanding role cells pathways underlying disease has become priority. Induced pluripotent stem cell (iPSC) technology helping uncover mechanisms develop RPE diseases, like bestrophinopathies. Here, we provide comprehensive review pathophysiology highlight how patient-derived iPSC-RPE being used test new genomic therapies vitro.

Language: Английский

Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell–Derived Retinal Pigment Epithelial Cells DOI Creative Commons
Sunao Sugita, Kenichi Makabe,

Yuko Iwasaki

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2018, Volume and Issue: 59(5), P. 1719 - 1719

Published: April 2, 2018

Purpose: To determine whether human induced pluripotent stem (iPS) cell–derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation. Methods: iPS-RPE were cocultured with peripheral blood mononuclear (PBMCs) or purified NK from healthy donors after stimulation cytokines. confirm expression of cell–specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) performed. (or PBMCs) assessed for proliferation by Ki-67 cytometry, suppression RPE was granzyme B production ELISA. Human leukocyte antigen (HLA) including HLA-E on evaluated qRT-PCR. The effect downregulation also investigated using small interfering RNA (siRNA) systems. Following transplantation in vivo, we invasion the retina immunohistochemistry. Results: Activated expressed NK-related markers such as CD16, CD56, CD11b, produced cytotoxic agents B, perforin, TNF-α. inhibited these activated vitro. constitutively suppressed activation through an interaction between CD94/NKG2A. Moreover, immunohistochemical evaluation monkey into vivo immune rejection models showed no allografts xenografts except one xenografted eye. Conclusions: Cultured iPS greatly Thus, might be inactivated when exposed to this type cell.

Language: Английский

Citations

30
Mutation spectrum of the bestrophin-1 gene in a large Chinese cohort with bestrophinopathy DOI

Fengjuan Gao,

Yu-He Qi,

Fangyuan Hu

et al.

British Journal of Ophthalmology, Journal Year: 2019, Volume and Issue: 104(6), P. 846 - 851

Published: Sept. 13, 2019

Background Bestrophin-1 ( BEST1 ) gene is associated with a wide range of ocular phenotypes, collectively termed as bestrophinopathy. The aim the current study was to identify mutation spectrum in large cohort Chinese patients Methods Patients clinically suspected bestrophinopathy were screened using multigene panel testing. All variants confirmed by Sanger sequencing, and validated families. Findings A total 92 (Best vitelliform macular dystrophy (BVMD)=77; autosomal recessive (ARB)=15) from 58 unrelated families origin their available family members (n=65) recruited. Overall, 39 distinct disease-causing identified, including 13 novel variants, two reported but for ARB. Of them, 14 ARB, 23 BVMD (c.604C>T c.898G>A) both Most mutations missense (97.78%), while ARB more complex mutations, (88.46%), splicing effect (3.85%), frameshifts (15.38%). hotspots c.898G>A c.584C>T among patients, respectively. Hot regions located exons 8, 2 6 5 7 patients. overall penetrance our 71.30%, no de novo identified. Conclusion This largest date that provides major population-based data China. Our results can serve well-founded reference genetic counselling origin.

Language: Английский

Citations

28
MERTK-Dependent Ensheathment of Photoreceptor Outer Segments by Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium DOI Creative Commons
Seba Almedawar,

Katerina Vafia,

Sven Schreiter

et al.

Stem Cell Reports, Journal Year: 2020, Volume and Issue: 14(3), P. 374 - 389

Published: March 1, 2020

Maintenance of a healthy photoreceptor-retinal pigment epithelium (RPE) interface is essential for vision. At the center this interface, apical membrane protrusions stemming from RPE ensheath photoreceptor outer segments (POS), and are possibly involved in recycling POS through phagocytosis. The molecules that regulate ensheathment its relationship to phagocytosis remain be deciphered. By means ultrastructural analysis, we revealed Mer receptor tyrosine kinase (MERTK) ligands, GAS6 PROS1, rather than αVβ5 integrin triggered by human embryonic stem cell (hESC)-derived RPE. Furthermore, found required fragmentation before internalization. Consistently, ensheathment, fragmentation, internalization were abolished MERTK mutant RPE, rescue expression retinitis pigmentosa (RP38) patient counteracted these defects. Our results suggest loss due dysfunction might contribute vision impairment RP38 patients.

Language: Английский

Citations

26
Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients DOI Open Access
Jingyi Luo, Mingkai Lin, Xinxing Guo

et al.

Acta Ophthalmologica, Journal Year: 2018, Volume and Issue: 97(3), P. 247 - 259

Published: Dec. 28, 2018

Abstract Purpose The aim of this study was to describe the genetic and clinical characteristics Chinese patients with autosomal recessive bestrophinopathy ( ARB ). Methods This presents a retrospective observational case series. Twenty‐one 25 clinically healthy family members were recruited. coding regions adjacent intronic BEST 1 analysed via Sanger sequencing. Clinical examinations, including ultrasound biomicroscopy, A‐scan, optical coherence tomography, fundus autofluorescence, fluorescein angiography FFA ), indocyanine green ICGA ) visual electrophysiology, reviewed. Results Six novel mutations (c.380C>T, p.T127M; c.397A>G, p.N133D; c.500A>G, p.E167G; c.817G>A, p.V273M; c.174_176del, p.Q58del; c.950_955del, p.S318_L319) 8 previously reported identified. p.R255W mutation had highest frequency in our cohort. Twenty serous retinal detachment multifocal subretinal vitelliform deposits posterior poles. One patient exhibited chorioretinal atrophy. revealed peripheral vascular leakage 10 patients, hyperfluorescent spots patients. Visual electrophysiology abnormal all Fifteen angle closure AC or angle‐closure glaucoma ACG shallower anterior chambers shorter axial lengths than open angle, contributing their risk developing / . developed during 7‐year follow‐up period. misdiagnosis missed rates 35.3% 58.8%, respectively. Conclusion six high suggest ethnical differences spectrum among gene screening detailed examinations help establishing diagnosis evaluations are recommended for

Language: Английский

Citations

25
Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies DOI Creative Commons
S. Grewal, Joseph J. Smith, Amanda‐Jayne F. Carr

et al.

Therapeutic Advances in Ophthalmology, Journal Year: 2021, Volume and Issue: 13

Published: Jan. 1, 2021

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum disorders is caused by mutations in bestrophin1 (BEST1), protein thought to act as Ca2+-activated Cl- channel pigment epithelium (RPE) eye. Although bestrophinopathies rare, over 250 individual pathological have been identified BEST1 gene, many reported various clinical expressivity and incomplete penetrance. With no current treatments available for patients bestrophinopathies, understanding role cells pathways underlying disease has become priority. Induced pluripotent stem cell (iPSC) technology helping uncover mechanisms develop RPE diseases, like bestrophinopathies. Here, we provide comprehensive review pathophysiology highlight how patient-derived iPSC-RPE being used test new genomic therapies vitro.

Language: Английский

Citations

19