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

Lookup NU author(s): Rob Atkinson, Dr Maria Georgiou, Dr Chunbo Yang, Marina Moya Molina, Dr Joseph Collin, Dr Rachel Queen, Avril Watson, Dr Marzena Kurzawa-Akanbi, Ross LawsORCiD, Abhijit Saxena, Chia Shyan Beh Beh, Chileleko Siachisumo, Tracey DaveyORCiD, Professor David SteelORCiD, Professor David Elliott, Professor Lyle Armstrong, Professor Majlinda LakoORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2024.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.

Publication metadata

Author(s): Atkinson R, Georgiou M, Yang C, Szymanska K, Lahat A, Vasconcelos EJR, Ji Y, Moya Molina M, Collin J, Queen R, Dorgau B, Watson A, Kurzawa-Akanbi M, Laws R, Saxena A, Shyan Beh C, Siachisumo C, Goertler F, Karwatka M, Davey T, Inglehearn CF, McKibbin M, Luhrmann R, Steel DH, Elliott DJ, Armstrong L, Urlaub H, Ali RR, Grellscheid S-N, Johnson CA, Mozaffari-Jovin S, Lako M

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2024

Volume: 15

Issue: 1

Online publication date: 11/04/2024

Acceptance date: 19/03/2024

Date deposited: 18/04/2024

ISSN (electronic): 2041-1723

Publisher: Nature Research


DOI: 10.1038/s41467-024-47253-0


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Funder referenceFunder name
BB/M012093/1Biotechnology and Biological Sciences Research Council (BBSRC)
BB/R013942/1Biotechnology and Biological Sciences Research Council (BBSRC)
MR/T017503/1Medical Research Council (MRC)