PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects

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 Watson, Marzena Kurzawa-Akanbi, Ross Laws, Abhijit Saxena, Chia Shyan Beh, Chileleko Siachisumo, Franziska Goertler, Magdalena Karwatka, Tracey Davey, Chris F. Inglehearn, Martin McKibbin, Reinhard Lührmann, David H. Steel, David J. Elliott, Lyle Armstrong, Henning Urlaub, Robin R. Ali, Sushma-Nagaraja Grellscheid, Colin A. Johnson (), Sina Mozaffari-Jovin () and Majlinda Lako ()
Additional contact information
Robert Atkinson: Newcastle University
Maria Georgiou: Newcastle University
Chunbo Yang: Newcastle University
Katarzyna Szymanska: University of Leeds
Albert Lahat: Durham University
Elton J. R. Vasconcelos: University of Leeds
Yanlong Ji: Max-Planck-Institute for Multidisciplinary Sciences
Marina Moya Molina: Newcastle University
Joseph Collin: Newcastle University
Rachel Queen: Newcastle University
Birthe Dorgau: Newcastle University
Avril Watson: Newcastle University
Marzena Kurzawa-Akanbi: Newcastle University
Ross Laws: Newcastle University
Abhijit Saxena: Newcastle University
Chia Shyan Beh: Newcastle University
Chileleko Siachisumo: Newcastle University
Franziska Goertler: University of Bergen
Magdalena Karwatka: University of Leeds
Tracey Davey: Newcastle University
Chris F. Inglehearn: University of Leeds
Martin McKibbin: University of Leeds
Reinhard Lührmann: Max-Planck-Institute for Multidisciplinary Sciences
David H. Steel: Newcastle University
David J. Elliott: Newcastle University
Lyle Armstrong: Newcastle University
Henning Urlaub: Max-Planck-Institute for Multidisciplinary Sciences
Robin R. Ali: Kings College London
Sushma-Nagaraja Grellscheid: Durham University
Colin A. Johnson: University of Leeds
Sina Mozaffari-Jovin: Max-Planck-Institute for Multidisciplinary Sciences
Majlinda Lako: Newcastle University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

Date: 2024
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DOI: 10.1038/s41467-024-47253-0

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