De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa
Authors: Quinodoz Mathieu , Rodenburg Kim , Cvackova Zuzana , Kaminska Karolina , de Bruijn Suzanne E , Iglesias-Romero Ana Belén , Boonen Erica G M , Ullah Mukhtar , Zomer Nick , Folcher Marc , Bijon Jacques , Holtes Lara K , Tsang Stephen H , Corradi Zelia , Freund K Bailey , Shliaga Stefanida , Panneman Daan M , Hitti-Malin Rebekkah J , Ali Manir , AlTalbishi Ala’a , Andréasson Sten , Ansari Georg , Arno Gavin , Astuti Galuh D N , Ayuso Carmen , Ayyagari Radha , Banfi Sandro , Banin Eyal , Barboni Mirella T S , Bauwens Miriam , Ben-Yosef Tamar , Birch David G , Biswas Pooja , Blanco-Kelly Fiona , Bocquet Beatrice , Boon Camiel J F , Branham Kari , Britten-Jones Alexis Ceecee , Bujakowska Kinga M , Cadena Elizabeth L , Calzetti Giacomo , Cancellieri Francesca , Cattaneo Luca , Issa Peter Charbel , Chadderton Naomi , Coutinho-Santos Luísa , Daiger Stephen P , De Baere Elfride , de la Cerda Berta , De Roach John N , De Zaeytijd Julie , Derks Ronny , Dhaenens Claire-Marie , Dudakova Lubica , Duncan Jacque L , Farrar G Jane , Feltgen Nicolas , Fernández-Caballero Lidia , Sallum Juliana M Ferraz , Gana Simone , Garanto Alejandro , Gardner Jessica C , Gilissen Christian , Goto Kensuke , Gonzàlez-Duarte Roser , Griffiths-Jones Sam , Haack Tobias B , Haer-Wigman Lonneke , Hardcastle Alison J , Hayashi Takaaki , Héon Elise , Hoischen Alexander , Holtan Josephine P , Hoyng Carel B , Ibanez Manuel Benjamin B , Inglehearn Chris F , Iwata Takeshi , Jones Kaylie , Kalatzis Vasiliki , Kamakari Smaragda , Karali Marianthi , Kellner Ulrich , Knézy Krisztina , Klaver Caroline C W , Koenekoop Robert K , Kohl Susanne , Kominami Taro , Kühlewein Laura , Lamey Tina M , Leroy Bart P , Martín-Gutiérrez María Pilar , Martins Nelson , Mauring Laura , Leibu Rina , Lin Siying , Liskova Petra , Lopez Irma , López-Rodríguez Victor R de J , Mahroo Omar A , Manes Gaël , McKibbin Martin , McLaren Terri L , Meunier Isabelle , Michaelides Michel , Millán José M , Mizobuchi Kei , Mukherjee Rajarshi , Nagy Zoltán Zsolt , Neveling Kornelia , Ołdak Monika , Oorsprong Michiel , Pan Yang , Papachristou Anastasia , Percesepe Antonio , Pfau Maximilian , Pierce Eric A , Place Emily , Ramesar Raj , Rasquin Florence Andrée , Rice Gillian I , Roberts Lisa , Rodríguez-Hidalgo María , Ruiz-Eddera Javier , Sabir Ataf H , Sajiki Ai Fujita , Sánchez-Barbero Ana Isabel , Sarma Asodu Sandeep , Sangermano Riccardo , Santos Cristina M , Scarpato Margherita , Scholl Hendrik P N , Sharon Dror , Signorini Sabrina Giovanna , Simonelli Francesca , Sousa Ana Berta , Stefaniotou Maria , Stingl Katarina , Suga Akiko , Sullivan Lori S , Szabó Viktória , Szaflik Jacek P , Taurina Gita , Toomes Carmel , Tran Viet H , Tsilimbaris Miltiadis K , Tsoka Pavlina , Vaclavik Veronika , Vajter Marie , Valeina Sandra , Valente Enza Maria , Valentine Casey , Valero Rebeca , van Aerschot Joseph , van den Born L. Ingeborgh , Webster Andrew R , Whelan Laura , Wissinger Bernd , Yioti Georgia G , Yoshitake Kazutoshi , Zenteno Juan C , Zeuli Roberta , Zuleger Theresia , Landau Chaim , Jacob Allan I , Cremers Frans P M , Lee Winston , Ellingford Jamie M , Stanek David , Rivolta Carlo , Roosing Susanne 
Published: January 2025

ABSTRACTThe U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrentde novovariants in the U4 RNA, transcribed from theRNU4-2gene, and in at least two otherRNUgenes were discovered to cause neurodevelopmental disorder. We detected inherited andde novoheterozygous variants inRNU4-2(n.18_19insA and n.56T>C) and in four out of the fiveRNU6paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants inRNU4-2and inRNU6paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy inRNU4-2, where different variants underlie neurodevelopmental disorder and RP.