Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.
Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.
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DOI：
10.1038/s41467-018-06448-y
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发表时间：
2018-10-12
影响因子：
16.6
通讯作者：
Lako M
中科院分区：
文献类型：
--
作者：
Buskin A;Zhu L;Chichagova V;Basu B;Mozaffari-Jovin S;Dolan D;Droop A;Collin J;Bronstein R;Mehrotra S;Farkas M;Hilgen G;White K;Pan KT;Treumann A;Hallam D;Bialas K;Chung G;Mellough C;Ding Y;Krasnogor N;Przyborski S;Zwolinski S;Al-Aama J;Alharthi S;Xu Y;Wheway G;Szymanska K;McKibbin M;Inglehearn CF;Elliott DJ;Lindsay S;Ali RR;Steel DH;Armstrong L;Sernagor E;Urlaub H;Pierce E;Lührmann R;Grellscheid SN;Johnson CA;Lako M
前mRNA加工因子（PRPF）突变导致常染色体显性视网膜色素变性（RP），但目前尚不清楚为什么普遍表达的基因突变导致非综合征性视网膜疾病。在这里，我们从RP 11（PRPF 31突变）患者衍生的视网膜类器官和视网膜色素上皮（RPE）以及Prpf 31 +/−小鼠组织中生成转录组图谱，这表明特定剪接程序发生了中断的选择性剪接。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Prpf 31 +/−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，包括破坏顶-基底极性、降低的跨上皮抗性和吞噬能力以及降低的纤毛长度和发病率。破坏的纤毛形态也发生在患者来源的光感受器中，与进行性变性和细胞应激相关。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。前mRNA加工因子的突变导致常染色体显性视网膜色素变性。在这里，作者提供了深入了解非综合征性视网膜疾病的病理生理机制引起的杂合突变的基因编码普遍表达的剪接因子。
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. Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1083/jcb.201004104
发表时间：
2010-05-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Linkert M;Rueden CT;Allan C;Burel JM;Moore W;Patterson A;Loranger B;Moore J;Neves C;Macdonald D;Tarkowska A;Sticco C;Hill E;Rossner M;Eliceiri KW;Swedlow JR
通讯作者：
Swedlow JR
影响因子：
3.4
作者：
Becerra, SP;Fariss, RN;Pfeffer, BA
通讯作者：
Pfeffer, BA
影响因子：
56.9
作者：
CACERES, JF;STAMM, S;KRAINER, AR
通讯作者：
KRAINER, AR