Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa

被引：161

作者：

Buskin, Adriana ^{[1
]}

Zhu, Lili ^{[1
]}

Chichagova, Valeria ^{[1
]}

Basu, Basudha ^{[2
]}

Mozaffari-Jovin, Sina ^{[3
]}

Dolan, David ^{[4
]}

Droop, Alastair ^{[5
]}

Collin, Joseph ^{[1
]}

Bronstein, Revital ^{[6
]}

Mehrotra, Sudeep ^{[6
]}

Farkas, Michael ^{[7
,8
]}

Hilgen, Gerrit ^{[9
]}

White, Kathryn ^{[10
]}

Pan, Kuan-Ting ^{[3
]}

Treumann, Achim ^{[11
]}

Hallam, Dean ^{[1
]}

Bialas, Katarzyna ^{[1
]}

Chung, Git ^{[12
]}

Mellough, Carla ^{[1
]}

Ding, Yuchun ^{[13
]}

Krasnogor, Natalio ^{[13
]}

Przyborski, Stefan ^{[4
]}

Zwolinski, Simon ^{[1
]}

Al-Aama, Jumana ^{[14
]}

Alharthi, Sameer ^{[14
]}

Xu, Yaobo ^{[1
]}

Wheway, Gabrielle ^{[15
]}

Szymanska, Katarzyna ^{[2
]}

McKibbin, Martin ^{[2
]}

Inglehearn, Chris F. ^{[2
]}

Elliott, David J. ^{[1
]}

Lindsay, Susan ^{[1
]}

Ali, Robin R. ^{[16
]}

Steel, David H. ^{[1
]}

Armstrong, Lyle ^{[1
]}

Sernagor, Evelyne ^{[9
]}

Urlaub, Henning ^{[17
]}

Pierce, Eric ^{[6
]}

Luehrmann, Reinhard ^{[3
]}

Grellscheid, Sushma-Nagaraja ^{[4
,18
]}

Johnson, Colin A. ^{[2
]}

Lako, Majlinda ^{[1
]}

机构：

[1] Newcastle Univ, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[2] Univ Leeds, St Jamess Univ Hosp, Leeds Inst Med Res, Beckett St, Leeds LS9 7TF, W Yorkshire, England

[3] Max Planck Inst Biophys Chem, Dept Cellular Biochem, Fassberg 11, D-37077 Gottingen, Germany

[4] Univ Durham, Dept Biol Sci, South Rd, Durham DH1 3LE, England

[5] Univ Leeds, MRC Med Bioinformat Ctr, Clarendon Way, Leeds LS2 9JT, W Yorkshire, England

[6] Mass Eye & Ear & Harvard Med Sch, Ocular Genom Inst, 243 Charles St, Boston, MA 02114 USA

[7] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Dept Ophthalmol, 955 Main St, Buffalo, NY 14203 USA

[8] SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Dept Biochem, 955 Main St, Buffalo, NY 14203 USA

[9] Newcastle Univ, Med Sch, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[10] Newcastle Univ, Med Sch, Electron Microscopy Res Serv, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[11] Newcastle Univ, Med Sch, Inst Cell & Mol Biosci, Catherine Cookson Bldg,Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[12] NUPPA, Devonshire Bldg,Devonshire Terrace, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[13] Newcastle Univ, Sch Comp, Interdisciplinary Comp & Complex Biosyst ICOS Res, Urban Sci Bldg,1 Sci Sq, Newcastle Upon Tyne NE4 5TG, Tyne & Wear, England

[14] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, 7393 Al Malaeb St, Jeddah 22252, Saudi Arabia

[15] Univ W England, Ctr Res Biosci, Frenchay Campus,Coldharbour Lane, Bristol BS16 1QY, Avon, England

[16] UCL Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England

[17] Max Planck Inst Biophys Chem, Bioanalyt Mass Spectrometry Grp, Fassberg 11, D-37077 Gottingen, Germany

[18] Univ Bergen, Dept Biol Sci, Computat Biol Unit, Thormohlensgt 55, N-5008 Bergen, Norway

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

EPITHELIUM-DERIVED FACTOR; TARGETED MOUSE MODELS; IN-VIVO; MUTATIONS; EXPRESSION; CELLS; PROTEIN; SECRETION; FAMILIES; HOMOLOG;

D O I：

10.1038/s41467-018-06448-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause nonsyndromic 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.

引用

页数：19

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