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

Adriana Buskin; Lili Zhu; Valeria Chichagova; Basudha Basu; Sina Mozaffari-Jovin; David Dolan; Alastair Droop; Joseph Collin; Revital Bronstein; Sudeep Mehrotra; Michael Farkas; Gerrit Hilgen; Kathryn White; Kuan Ting Pan; Achim Treumann; Dean Hallam; Katarzyna Bialas; Git Chung; Carla Mellough; Yuchun Ding; Natalio Krasnogor; Stefan Przyborski; Simon Zwolinski; Jumana Al-Aama; Sameer Alharthi; Yaobo Xu; Gabrielle Wheway; Katarzyna Szymanska; Martin McKibbin; Chris F. Inglehearn; David J. Elliott; Susan Lindsay; Robin R. Ali; David H. Steel; Lyle Armstrong; Evelyne Sernagor; Henning Urlaub; Eric Pierce; Reinhard Lührmann; Sushma Nagaraja Grellscheid; Colin A. Johnson; Majlinda Lako

doi:10.1038/s41467-018-06448-y

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

Adriana Buskin, Lili Zhu, Valeria Chichagova, Basudha Basu, Sina Mozaffari-Jovin, David Dolan, Alastair Droop, Joseph Collin, Revital Bronstein, Sudeep Mehrotra, Michael Farkas, Gerrit Hilgen, Kathryn White, Kuan Ting Pan, Achim Treumann, Dean Hallam, Katarzyna Bialas, Git Chung, Carla Mellough, Yuchun DingNatalio Krasnogor, Stefan Przyborski, Simon Zwolinski, Jumana Al-Aama, Sameer Alharthi, Yaobo Xu, Gabrielle Wheway, Katarzyna Szymanska, Martin McKibbin, Chris F. Inglehearn, David J. Elliott, Susan Lindsay, Robin R. Ali, David H. Steel, Lyle Armstrong, Evelyne Sernagor, Henning Urlaub, Eric Pierce, Reinhard Lührmann, Sushma Nagaraja Grellscheid, Colin A. Johnson, Majlinda Lako^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	4234
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	12 Oct 2018
DOIs	https://doi.org/10.1038/s41467-018-06448-y
Publication status	Published - 1 Dec 2018
Externally published	Yes

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s41467-018-06448-yFinal published version, 11.2 MBLicence: CC BY

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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, K. T., Treumann, A., Hallam, D., Bialas, K., Chung, G., Mellough, C., ... Lako, M. (2018). Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nature Communications, 9(1), Article 4234. https://doi.org/10.1038/s41467-018-06448-y

@article{a2cf8fd572aa43f5a698fe3ed4d4c854,

title = "Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa",

abstract = "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.",

author = "Adriana Buskin and Lili Zhu and Valeria Chichagova and Basudha Basu and Sina Mozaffari-Jovin and David Dolan and Alastair Droop and Joseph Collin and Revital Bronstein and Sudeep Mehrotra and Michael Farkas and Gerrit Hilgen and Kathryn White and Pan, {Kuan Ting} and Achim Treumann and Dean Hallam and Katarzyna Bialas and Git Chung and Carla Mellough and Yuchun Ding and Natalio Krasnogor and Stefan Przyborski and Simon Zwolinski and Jumana Al-Aama and Sameer Alharthi and Yaobo Xu and Gabrielle Wheway and Katarzyna Szymanska and Martin McKibbin and Inglehearn, {Chris F.} and Elliott, {David J.} and Susan Lindsay and Ali, {Robin R.} and Steel, {David H.} and Lyle Armstrong and Evelyne Sernagor and Henning Urlaub and Eric Pierce and Reinhard L{\"u}hrmann and Grellscheid, {Sushma Nagaraja} and Johnson, {Colin A.} and Majlinda Lako",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06448-y",

language = "English",

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journal = "Nature Communications",

issn = "2041-1723",

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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 2018, 'Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa', Nature Communications, vol. 9, no. 1, 4234. https://doi.org/10.1038/s41467-018-06448-y

TY - JOUR

T1 - Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa

AU - Buskin, Adriana

AU - Zhu, Lili

AU - Chichagova, Valeria

AU - Basu, Basudha

AU - Mozaffari-Jovin, Sina

AU - Dolan, David

AU - Droop, Alastair

AU - Collin, Joseph

AU - Bronstein, Revital

AU - Mehrotra, Sudeep

AU - Farkas, Michael

AU - Hilgen, Gerrit

AU - White, Kathryn

AU - Pan, Kuan Ting

AU - Treumann, Achim

AU - Hallam, Dean

AU - Bialas, Katarzyna

AU - Chung, Git

AU - Mellough, Carla

AU - Ding, Yuchun

AU - Krasnogor, Natalio

AU - Przyborski, Stefan

AU - Zwolinski, Simon

AU - Al-Aama, Jumana

AU - Alharthi, Sameer

AU - Xu, Yaobo

AU - Wheway, Gabrielle

AU - Szymanska, Katarzyna

AU - McKibbin, Martin

AU - Inglehearn, Chris F.

AU - Elliott, David J.

AU - Lindsay, Susan

AU - Ali, Robin R.

AU - Steel, David H.

AU - Armstrong, Lyle

AU - Sernagor, Evelyne

AU - Urlaub, Henning

AU - Pierce, Eric

AU - Lührmann, Reinhard

AU - Grellscheid, Sushma Nagaraja

AU - Johnson, Colin A.

AU - Lako, Majlinda

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054894609&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-06448-y

DO - 10.1038/s41467-018-06448-y

M3 - Article

C2 - 30315276

AN - SCOPUS:85054894609

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4234

ER -

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

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