Nava C, Cogne B, Santini A, Leitão E, Lecoquierre F, Chen Y, Stenton SL, Besnard T, Heide S, Baer S, Jakhar A, Neuser S, Keren B, Faudet A, Forlani S, Faoucher M, Uguen K, Platzer K, Afenjar A, Alessandri JL, Andres S, Angelini C, Aral B, Arveiler B, Attie-Bitach T, Aubert Mucca M, Banneau G, Barakat TS, Barcia G, Baulac S, Beneteau C, Benkerdou F, Bernard V, Bézieau S, Bonneau D, Bonnet-Dupeyron MN, Boussion S, Boute O, Brischoux-Boucher E, Bryen SJ, Buratti J, Busa T, Caliebe A, Capri Y, Cassinari K, Caumes R, Cenni C, Chambon P, Charles P, Christodoulou J, Colson C, Conrad S, Cospain A, Coursimault J, Courtin T, Couse M, Coutton C, Creveaux I, D’Gama AM, Dauriat B, de Sainte Agathe JM, Del Gobbo G, Delahaye-Duriez A, Delanne J, Denommé-Pichon AS, Dieux-Coeslier A, Do Souto Ferreira L, Doco-Fenzy M, Drukewitz S, Duboc V, Dubourg C, Duffourd Y, Dyment D, El Chehadeh S, Elmaleh M, Faivre L, Fennelly S, Fischer H, Fradin M, Galludec Vaillant C, Ganne B, Ghoumid J, Goel H, Gokce-Samar Z, Goldenberg A, Gonfreville Robert R, Gorokhova S, Goujon L, Granier V, Gras M, Greally JM, Greiten B, Gueguen P, Guerrot AM, Guha S, Guimier A, Haack TB, Hadj Abdallah H, Halleb Y, Harbuz R, Harris M, Hentschel J, Héron B, Hitz MP, Innes AM, Jadas V, Januel L, Jean-Marçais N, Jobanputra V, Jobic F, Jornea L, Jost C, Julia S, Kaiser FJ, Kaschta D, Kaya S, Ketteler P, Khadija B, Kilpert F, Knopp C, Kraft F, Krey I, Lackmy M, Laffargue F, Lambert L, Lamont R, Laugel V, Laurie S, Lauzon JL, Lebreton L, Lebrun M, Legendre M, Leguern E, Lehalle D, Lejeune E, Lesca G, Lesieur-Sebellin M, Levy J, Linglart A, Lyonnet S, Lüthy K, Ma AS, Mach C, Mandel JL, Mansour-Hendili L, Marcadier J, Marin V, Margot H, Marquet V, May A, Mayr JA, Meridda C, Michaud V, Michot C, Nadeau G, Naudion S, Nguyen L, Nizon M, Nowak F, Odent S, Olin V, Osei-Owusu IA, Osmond M, Õunap K, Pasquier L, Passemard S, Pauly M, Patat O, Pensec M, Perrin-Sabourin L, Petit F, Philippe C, Planes M, Poduri A, Poirsier C, Pouzet A, Prince B, Prouteau C, Pujol A, Racine C, Rama M, Ramond F, Ranguin K, Raway M, Reis A, Renaud M, Revencu N, Richard AC, Riera-Navarro L, Rius R, Rodriguez D, Rodriguez-Palmero A, Rondeau S, Roser-Unruh A, Rougeot Jung C, Safraou H, Satre V, Saugier-Veber P, Sauvestre C, Schaefer E, Shao W, Schanze I, Schlump JU, Schlüter Martin A, Schluth-Bolard C, Schuhmann S, Schröder C, Sebastin M, Sigaudy S, Spielmann M, Spodenkiewicz M, St Clair L, Steffann J, Stoeva R, Surowy H, Tarnopolsky MA, Todosi C, Toutain A, Tran Mau-Them F, Unterlauft A, Van-Gils J, Vanlerberghe C, Vasileiou G, Vera G, Verdel A, Verloes A, Vial Y, Vignal C, Vincent M, Vincent-Delorme C, Vincent-Devulder A, Vitobello A, Weber S, Willems M, Zaafrane-Khachnaoui K, Zacher P, Zeltner L, Ziegler A, Galej WP, Dollfus H, Thauvin C, Boycott KM, Marijon P, Lermine A, Malan V, Rio M, Kuechler A, Isidor B, Drunat S, Smol T, Chatron N, Piton A, Nicolas G, Wagner M, Abou Jamra R, Héron D, Mignot C, Blanc P, O’Donnell-Luria A, Whiffin N, Charbonnier C, Charenton C, Thevenon J, Depienne C (2025)
Publication Type: Journal article
Publication year: 2025
Article Number: e103777
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.
APA:
Nava, C., Cogne, B., Santini, A., Leitão, E., Lecoquierre, F., Chen, Y.,... Depienne, C. (2025). Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. Nature Genetics. https://doi.org/10.1038/s41588-025-02184-4
MLA:
Nava, Caroline, et al. "Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption." Nature Genetics (2025).
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