July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Human iPSC-derived RPE and retinal organoids reveal impaired alternative splicing of genes involved in pre-mRNA splicing in PRPF31 autosomal dominant retinitis pigmentosa
Author Affiliations & Notes
  • Majlinda Lako
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Adriana Buskin
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Lili Zhu
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Valeria Chichagova
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Basudha Basu
    Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
  • Sina Mozaffari-Jovin
    Max-Planck Institute of Biophysical Chemistry, Gottingen, Germany
  • David Dolan
    Department of Biological Sciences, , University of Durham, DUrham, United Kingdom
  • Alastair Droop
    MRC Medical Bioinformatics Centre, , University of Leeds, Leeds, United Kingdom
  • Joseph Collin
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Gerrit Hilgen
    Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom
  • Lyle Armstrong
    Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Evelyne Sernagor
    Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom
  • Reinhard Luehrmann
    Max-Planck Institute of Biophysical Chemistry, Gottingen, Germany
  • Sushma-Nagaraja Grellscheid
    Department of Biological Sciences, , University of Durham, DUrham, United Kingdom
  • Colin Johnson
    Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom
  • Footnotes
    Commercial Relationships   Majlinda Lako, None; Adriana Buskin, None; Lili Zhu, None; Valeria Chichagova, None; Basudha Basu, None; Sina Mozaffari-Jovin, None; David Dolan, None; Alastair Droop, None; Joseph Collin, None; Gerrit Hilgen, None; Lyle Armstrong, None; Evelyne Sernagor, None; Reinhard Luehrmann, None; Sushma-Nagaraja Grellscheid, None; Colin Johnson, None
  • Footnotes
    Support  The authors are grateful for financial support from Fight for Sight (1456/1457), ERC (CoG_614620 and 2012-ADG_20120314), RP Fighting Blindness (GR584), CiC (MC_PC_15030), SFB (860), Medical Research Council (MR/K011154/1, MR/M000532/1, MR/N005872/1),
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1563. doi:
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      Majlinda Lako, Adriana Buskin, Lili Zhu, Valeria Chichagova, Basudha Basu, Sina Mozaffari-Jovin, David Dolan, Alastair Droop, Joseph Collin, Gerrit Hilgen, Lyle Armstrong, Evelyne Sernagor, Reinhard Luehrmann, Sushma-Nagaraja Grellscheid, Colin Johnson; Human iPSC-derived RPE and retinal organoids reveal impaired alternative splicing of genes involved in pre-mRNA splicing in PRPF31 autosomal dominant retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1563.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinitis pigmentosa (RP) is one of the most common forms of hereditary, progressive sight loss, affecting more than 1 million people worldwide. Autosomal dominant inheritance accounts for about 40% of RP, with an estimated 38% of these caused by mutations in six pre-mRNA processing factors (PRPFs). PRPFs are ubiquitously expressed, but mutations only cause retinal-specific degeneration, raising the question of why retinal cells are more susceptible to splicing deficiencies.

Methods : In this study, we used fibroblasts from four patients with two different PRPF31 mutations (c.1115_1125del11 and c.522_527del6&IVS6+1to+10del) to derive induced pluripotent stem cells (iPSCs). Patient-specific iPSC and age-matched controls were differentiated into RPE and three dimensional retinal organoids in order to elucidate disease mechanisms and to identify cell-type and patient-specific target genes affected by PRPF31 mutations.

Results : Our data show that PRPF31 mutations result in impaired alternative splicing of genes encoding pre-mRNA splicing proteins in retinal cells, but not fibroblasts and iPSCs, providing mechanistic insights into retinal-specific phenotypes of PRPFs. These result in defective cilia, progressive degeneration, cell stress and impaired function in retinal pigmented epithelium (RPE) and photoreceptors.

Conclusions : Our data provide, for the first time, a mechanistic understanding of retinal-specific phenotypes in PRPF31-mutated RP patients. Our studies highlight the advantages of iPSC-based disease modelling for identifying the affected retinal cell types and target genes, and for testing potential targeted therapies.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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