| Title: |
Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption |
| Authors: |
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 |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2025 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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. ; 10.1038/s41588-025-02184-4 |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1061-4036 |
| Relation: |
https://hdl.handle.net/11343/363384 |
| Availability: |
https://hdl.handle.net/11343/363384 |
| Rights: |
https://creativecommons.org/licenses/by-nc-nd/4.0 ; CC BY-NC-ND |
| Accession Number: |
edsbas.F53B7EEA |
| Database: |
BASE |