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

Author

Listed:
  • Adriana Buskin

    (Newcastle University)

  • Lili Zhu

    (Newcastle University)

  • Valeria Chichagova

    (Newcastle University)

  • Basudha Basu

    (St James’s University Hospital)

  • Sina Mozaffari-Jovin

    (Max-Planck-Institute of Biophysical Chemistry)

  • David Dolan

    (Durham University)

  • Alastair Droop

    (University of Leeds)

  • Joseph Collin

    (Newcastle University)

  • Revital Bronstein

    (Mass Eye and Ear and Harvard Medical School)

  • Sudeep Mehrotra

    (Mass Eye and Ear and Harvard Medical School)

  • Michael Farkas

    (State University of New York at Buffalo)

  • Gerrit Hilgen

    (Newcastle University)

  • Kathryn White

    (Newcastle University)

  • Kuan-Ting Pan

    (Max-Planck-Institute of Biophysical Chemistry)

  • Achim Treumann

    (Newcastle University)

  • Dean Hallam

    (Newcastle University)

  • Katarzyna Bialas

    (Newcastle University)

  • Git Chung

    (Newcastle University Protein and Proteome Analysis (NUPPA))

  • Carla Mellough

    (Newcastle University)

  • Yuchun Ding

    (Newcastle University)

  • Natalio Krasnogor

    (Newcastle University)

  • Stefan Przyborski

    (Durham University)

  • Simon Zwolinski

    (Newcastle University)

  • Jumana Al-Aama

    (King Abdulaziz University)

  • Sameer Alharthi

    (King Abdulaziz University)

  • Yaobo Xu

    (Newcastle University)

  • Gabrielle Wheway

    (University of the West of England)

  • Katarzyna Szymanska

    (St James’s University Hospital)

  • Martin McKibbin

    (St James’s University Hospital)

  • Chris F. Inglehearn

    (St James’s University Hospital)

  • David J. Elliott

    (Newcastle University)

  • Susan Lindsay

    (Newcastle University)

  • Robin R. Ali

    (UCL Institute of Ophthalmology)

  • David H. Steel

    (Newcastle University)

  • Lyle Armstrong

    (Newcastle University)

  • Evelyne Sernagor

    (Newcastle University)

  • Henning Urlaub

    (Max-Planck-Institute for Biophysical Chemistry)

  • Eric Pierce

    (Mass Eye and Ear and Harvard Medical School)

  • Reinhard Lührmann

    (Max-Planck-Institute of Biophysical Chemistry)

  • Sushma-Nagaraja Grellscheid

    (Durham University
    University of Bergen)

  • Colin A. Johnson

    (St James’s University Hospital)

  • Majlinda Lako

    (Newcastle University)

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.

Suggested Citation

  • Adriana Buskin & Lili Zhu & Valeria Chichagova & Basudha Basu & Sina Mozaffari-Jovin & David Dolan & Alastair Droop & Joseph Collin & Revital Bronstein & Sudeep Mehrotra & Michael Farkas & Gerrit Hilg, 2018. "Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06448-y
    DOI: 10.1038/s41467-018-06448-y
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    Cited by:

    1. Robert Atkinson & Maria Georgiou & Chunbo Yang & Katarzyna Szymanska & Albert Lahat & Elton J. R. Vasconcelos & Yanlong Ji & Marina Moya Molina & Joseph Collin & Rachel Queen & Birthe Dorgau & Avril W, 2024. "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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