De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
Mathieu Quinodoz, Kim Rodenburg, Zuzana Cvačková, Karolina Kamińska, Suzanne E. de Bruijn, Ana Belén Iglesias-Romero, Erica G. M. Boonen, Mukhtar Ullah, Nick Zomer, Marc Folcher, Jacques Bijon, Lara K. Holtes, Stephen H. Tsang, Zelia Corradi, K. Bailey Freund, Stefanida Shliaga, Daan M. Panneman, Rebekkah J. Hitti-Malin, Manir Ali, Ala’a AlTalbishi, Sten Andréasson, Georg Ansari, Gavin Arno, Galuh D N Astuti, Carmen Ayuso, Radha Ayyagari, Sandro Banfi, Eyal Banin, Tahsin Stefan Barakat, Mirella T.S. Barboni, Miriam Bauwens, Tamar Ben‐Yosef, Virginie Bernard, David G. Birch, Pooja Biswas, Fiona Blanco‐Kelly, Béatrice Bocquet, Camiel J. F. Boon, Kari Branham, Dominique Bremond-Gignac, Alexis Ceecee Britten-Jones, Kinga M. Bujakowska, Cyril Burin des Roziers, Elizabeth L. Cadena, Giacomo Calzetti, Francesca Cancellieri, Luca Cattaneo, Naomi Chadderton, Peter Charbel Issa, Luísa Coutinho-Santos, Stephen P. Daiger, Elfride De Baere, Marieke De Bruyne, Berta de la Cerda, John N. De Roach, Julie De Zaeytijd, Ronny Derks, Claire‐Marie Dhaenens, Ľubica Ďuďáková, Jacque L. Duncan, G. Jane Farrar, Nicolas Feltgen, Beau J. Fenner, Lidia Fernández-Caballero, Juliana M. Ferraz Sallum, Simone Gana, Alejandro Garanto, Jessica C. Gardner, Christian Gilissen, Roser Gonzàlez-Duarte, Kensuke Goto, Sam Griffiths-Jones, Tobias B. Haack, Lonneke Haer-Wigman, Alison J. Hardcastle, Takaaki Hayashi, Elise Héon, Lies H. Hoefsloot, Alexander Hoischen, Josephine P. Holtan, Carel B. Hoyng, Manuel Benjamin B. Ibanez, Chris F. Inglehearn, Takeshi Iwata, Brynjar O. Jensson, Kaylie Jones, Vasiliki Kalatzis, Smaragda Kamakari, Marianthi Karali, Ulrich Kellner, Caroline C. W. Klaver, Krisztina Knézy, Robert K. Koenekoop, Susanne Kohl, Taro Kominami, Laura Kühlewein, Tina M. Lamey, Rina Leibu, Bart P. Leroy, Petra Liskova
Abstract
Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration. De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.