主要剪接体U4和U5小核RNA基因中的显性变异通过剪接破坏导致神经发育障碍。
Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption.
作者信息
Nava Caroline, Cogne Benjamin, Santini Amandine, Leitão Elsa, Lecoquierre François, Chen Yuyang, Stenton Sarah L, Besnard Thomas, Heide Solveig, Baer Sarah, Jakhar Abhilasha, Neuser Sonja, Keren Boris, Faudet Anne, Forlani Sylvie, Faoucher Marie, Uguen Kevin, Platzer Konrad, Afenjar Alexandra, Alessandri Jean-Luc, Andres Stephanie, Angelini Chloé, Aral Bernard, Arveiler Benoit, Attie-Bitach Tania, Aubert Mucca Marion, Banneau Guillaume, Barakat Tahsin Stefan, Barcia Giulia, Baulac Stéphanie, Beneteau Claire, Benkerdou Fouzia, Bernard Virginie, Bézieau Stéphane, Bonneau Dominique, Bonnet-Dupeyron Marie-Noelle, Boussion Simon, Boute Odile, Brischoux-Boucher Elise, Bryen Samantha J, Buratti Julien, Busa Tiffany, Caliebe Almuth, Capri Yline, Cassinari Kévin, Caumes Roseline, Cenni Camille, Chambon Pascal, Charles Perrine, Christodoulou John, Colson Cindy, Conrad Solène, Cospain Auriane, Coursimault Juliette, Courtin Thomas, Couse Madeline, Coutton Charles, Creveaux Isabelle, D'Gama Alissa M, Dauriat Benjamin, de Sainte Agathe Jean-Madeleine, Del Gobbo Giulia, Delahaye-Duriez Andrée, Delanne Julian, Denommé-Pichon Anne-Sophie, Dieux-Coeslier Anne, Do Souto Ferreira Laura, Doco-Fenzy Martine, Drukewitz Stephan, Duboc Véronique, Dubourg Christèle, Duffourd Yannis, Dyment David, El Chehadeh Salima, Elmaleh Monique, Faivre Laurence, Fennelly Samuel, Fischer Hanna, Fradin Mélanie, Galludec Vaillant Camille, Ganne Benjamin, Ghoumid Jamal, Goel Himanshu, Gokce-Samar Zeynep, Goldenberg Alice, Gonfreville Robert Romain, Gorokhova Svetlana, Goujon Louise, Granier Victoria, Gras Mathilde, Greally John M, Greiten Bianca, Gueguen Paul, Guerrot Anne-Marie, Guha Saurav, Guimier Anne, Haack Tobias B, Hadj Abdallah Hamza, Halleb Yosra, Harbuz Radu, Harris Madeleine, Hentschel Julia, Héron Bénédicte, Hitz Marc-Phillip, Innes A Micheil, Jadas Vincent, Januel Louis, Jean-Marçais Nolwenn, Jobanputra Vaidehi, Jobic Florence, Jornea Ludmila, Jost Céline, Julia Sophie, Kaiser Frank J, Kaschta Daniel, Kaya Sabine, Ketteler Petra, Khadija Bochra, Kilpert Fabian, Knopp Cordula, Kraft Florian, Krey Ilona, Lackmy Marilyn, Laffargue Fanny, Lambert Laetitia, Lamont Ryan, Laugel Vincent, Laurie Steven, Lauzon Julie L, Lebreton Louis, Lebrun Marine, Legendre Marine, Leguern Eric, Lehalle Daphné, Lejeune Elodie, Lesca Gaetan, Lesieur-Sebellin Marion, Levy Jonathan, Linglart Agnès, Lyonnet Stanislas, Lüthy Kevin, Ma Alan S, Mach Corinne, Mandel Jean-Louis, Mansour-Hendili Lamisse, Marcadier Julien, Marin Victor, Margot Henri, Marquet Valentine, May Angèle, Mayr Johannes A, Meridda Catherine, Michaud Vincent, Michot Caroline, Nadeau Gwenael, Naudion Sophie, Nguyen Laetitia, Nizon Mathilde, Nowak Frédérique, Odent Sylvie, Olin Valerie, Osei-Owusu Ikeoluwa A, Osmond Matthew, Õunap Katrin, Pasquier Laurent, Passemard Sandrine, Pauly Melissa, Patat Olivier, Pensec Marine, Perrin-Sabourin Laurence, Petit Florence, Philippe Christophe, Planes Marc, Poduri Annapurna, Poirsier Céline, Pouzet Antoine, Prince Bradley, Prouteau Clément, Pujol Aurora, Racine Caroline, Rama Mélanie, Ramond Francis, Ranguin Kara, Raway Margaux, Reis André, Renaud Mathilde, Revencu Nicole, Richard Anne-Claire, Riera-Navarro Lucile, Rius Rocio, Rodriguez Diana, Rodriguez-Palmero Agustí, Rondeau Sophie, Roser-Unruh Annika, Rougeot Jung Christelle, Safraou Hana, Satre Véronique, Saugier-Veber Pascale, Sauvestre Clément, Schaefer Elise, Shao Wanqing, Schanze Ina, Schlump Jan-Ulrich, Schlüter Martin Agatha, Schluth-Bolard Caroline, Schuhmann Sarah, Schröder Christopher, Sebastin Monisha, Sigaudy Sabine, Spielmann Malte, Spodenkiewicz Marta, St Clair Laura, Steffann Julie, Stoeva Radka, Surowy Harald, Tarnopolsky Mark A, Todosi Calina, Toutain Annick, Tran Mau-Them Frédéric, Unterlauft Astrid, Van-Gils Julien, Vanlerberghe Clémence, Vasileiou Georgia, Vera Gabriella, Verdel André, Verloes Alain, Vial Yoann, Vignal Cédric, Vincent Marie, Vincent-Delorme Catherine, Vincent-Devulder Aline, Vitobello Antonio, Weber Sacha, Willems Marjolaine, Zaafrane-Khachnaoui Khaoula, Zacher Pia, Zeltner Lena, Ziegler Alban, Galej Wojciech P, Dollfus Hélène, Thauvin Christel, Boycott Kym M, Marijon Pierre, Lermine Alban, Malan Valérie, Rio Marlène, Kuechler Alma, Isidor Bertrand, Drunat Séverine, Smol Thomas, Chatron Nicolas, Piton Amélie, Nicolas Gael, Wagner Matias, Abou Jamra Rami, Héron Delphine, Mignot Cyril, Blanc Pierre, O'Donnell-Luria Anne, Whiffin Nicola, Charbonnier Camille, Charenton Clément, Thevenon Julien, Depienne Christel
机构信息
Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne Université, Département de Génétique Médicale, Hôpital Pitié-Salpêtrière, Paris, France.
出版信息
Nat Genet. 2025 May 16. doi: 10.1038/s41588-025-02184-4.
The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.
主要剪接体包含五种对剪接至关重要的小核RNA（snRNA；U1、U2、U4、U5和U6）。编码U4的RNU4 - 2中的变异会导致一种名为ReNU综合征的神经发育障碍。我们在一个由23649名患有罕见疾病的个体组成的法国队列中，对50个编码snRNA的基因中的新生变异进行了研究，并通过国际合作收集了更多病例。我们总共鉴定出145名先前未报告的先证者，其RNU4 - 2中存在（可能）致病变异，以及21名在编码U5的RNU5B - 1和RNU5A - 1中存在新生和/或反复出现变异的个体。致病变异通常在母本等位基因上新生出现，并聚集在对剪接至关重要的区域。RNU4 - 2变异主要定位于两个结构，即茎III和T环/准假结，它们将U6 ACAGAGA框定位用于5'剪接位点识别，并与不同的表型严重程度相关。RNU4 - 2变异导致选择性5'剪接位点使用和甲基化模式（表型特征）出现特定缺陷，这些缺陷与变异位置和临床严重程度相关。这项研究确定RNU5B - 1为神经发育障碍基因，表明RNU5A - 1是一个强有力的候选基因，并突出了snRNA中新生变异的作用。
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