Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.,Nature Communications

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Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.
Nature Communications ( IF 14.7 ) Pub Date : 2018-10-12 , DOI: 10.1038/s41467-018-06448-y
Adriana Buskin ₁ , Lili Zhu ₁ , Valeria Chichagova ₁ , Basudha Basu ₂ , Sina Mozaffari-Jovin ₃ , David Dolan ₄ , Alastair Droop ₅ , Joseph Collin ₁ , Revital Bronstein ₆ , Sudeep Mehrotra ₆ , Michael Farkas ₇ , Gerrit Hilgen ₈ , Kathryn White ₉ , Kuan-Ting Pan ₃ , Achim Treumann ₁₀ , Dean Hallam ₁ , Katarzyna Bialas ₁ , Git Chung ₁₁ , Carla Mellough ₁ , Yuchun Ding ₁₂ , Natalio Krasnogor ₁₂ , Stefan Przyborski ₄ , Simon Zwolinski ₁ , Jumana Al-Aama ₁₃ , Sameer Alharthi ₁₃ , Yaobo Xu ₁ , Gabrielle Wheway ₁₄ , Katarzyna Szymanska ₂ , Martin McKibbin ₂ , Chris F Inglehearn ₂ , David J Elliott ₁ , Susan Lindsay ₁ , Robin R Ali ₁₅ , David H Steel ₁ , Lyle Armstrong ₁ , Evelyne Sernagor ₈ , Henning Urlaub ₁₆ , Eric Pierce ₆ , Reinhard Lührmann ₃ , Sushma-Nagaraja Grellscheid _{4,

17} , Colin A Johnson ₂ , Majlinda Lako ₁

Affiliation

Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
Leeds Institute of Medical Research, University of Leeds, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK.
Department of Cellular Biochemistry, Max-Planck-Institute of Biophysical Chemistry, Am Fassberg 11, Goettingen, D-37077, Germany.
Department of Biological Sciences, Durham University, South Road, Durham, DH1 3LE, UK.
MRC Medical Bioinformatics Centre, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK.
Ocular Genomics Institute, Mass Eye and Ear and Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA.
Departments of Ophthalmology and Biochemistry, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, 955 Main Street, Buffalo, NY, 14203-1121, USA.
Institute of Neuroscience, Medical School, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Electron Microscopy Research Services, Medical School, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Catherine Cookson Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Newcastle University Protein and Proteome Analysis (NUPPA), Devonshire Building, Devonshire Terrace, Newcastle upon Tyne, NE1 7RU, UK.
Interdisciplinary Computing and Complex Biosystems (ICOS) Research Group, School of Computing, Newcastle University, Urban Sciences Building, 1 Science Square, Newcastle Helix, Newcastle upon Tyne, NE4 5TG, UK.
Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, 7393 Al-Malae'b St, Jeddah, 22252, Saudi Arabia.
Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol, BS16 1QY, UK.
UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.
Bioanalytical Mass Spectrometry Group, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, Goettingen, D-37077, Germany.
Computational Biology Unit, Department of Biological Sciences, University of Bergen, Thormohlensgt 55, Bergen, N-5008, Norway.

Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31^+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31^+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical - basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.

中文翻译：

与剪接和纤毛发生相关的基因的选择性剪接被破坏会导致 PRPF31 视网膜色素变性。

前 mRNA 加工因子 (PRPF) 的突变会导致常染色体显性遗传性视网膜色素变性 (RP)，但目前尚不清楚为什么普遍表达的基因的突变会导致非综合征性视网膜疾病。在这里，我们从 RP11（PRPF31 突变）患者来源的视网膜类器官和视网膜色素上皮 (RPE) 以及 Prpf31 ^+/-小鼠组织中生成转录组图谱，这表明特定剪接程序发生了破坏的选择性剪接。编码前 mRNA 剪接蛋白的基因的错误剪接仅限于患者特异性视网膜细胞和 Prpf31 ^+/-小鼠视网膜和 RPE。与纤毛发生和细胞粘附有关的基因的错误剪接与严重的 RPE 缺陷相关，包括顶端 - 基底极性破坏、跨上皮阻力和吞噬能力降低以及纤毛长度和发生率降低。患者来源的光感受器中也发生了纤毛形态的破坏，这与进行性退化和细胞应激有关。致病突变的原位基因编辑挽救了 RPE 和光感受器中的蛋白质表达和关键细胞表型，为未来的治疗策略提供了概念证明。

更新日期：2018-10-12

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