Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy

The major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we repor...

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Autores: Greene, Daniel, Sevilla-Porras, Marta, Pérez Jurado, Luis Alberto, Turro, Ernest
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:dnet:recercat____::15702a07c5acc393a6e879348936399c
Acceso en línea:https://hdl.handle.net/10230/73390
http://dx.doi.org/10.1038/s41588-025-02159-5
Access Level:acceso abierto
Palabra clave:Neurodevelopmental disorders
Sequencing
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spelling Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsyGreene, DanielSevilla-Porras, MartaPérez Jurado, Luis AlbertoTurro, ErnestNeurodevelopmental disordersSequencingThe major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder. By genetic association, we identified recurrent de novo single-nucleotide mutations at nucleotide positions 4 and 35 of RNU2-2 in nine cases. We replicated this finding in 16 additional cases, bringing the total to 25. We estimate that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome. The disorder is characterized by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype. We found that U2-2 and canonical U2-1 were similarly expressed in blood. Despite mutant U2-2 being expressed in patient blood samples, we found no evidence of missplicing. Our findings cement the role of major spliceosomal snRNAs in the etiologies of neurodevelopmental disorders.Nature Research2026202620252026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/10230/73390http://dx.doi.org/10.1038/s41588-025-02159-5https://hdl.handle.net/10230/73390reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNature Genetics. 2025;57(6):1367-73© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:dnet:recercat____::15702a07c5acc393a6e879348936399c2026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
title Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
spellingShingle Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
Greene, Daniel
Neurodevelopmental disorders
Sequencing
title_short Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
title_full Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
title_fullStr Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
title_full_unstemmed Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
title_sort Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy
dc.creator.none.fl_str_mv Greene, Daniel
Sevilla-Porras, Marta
Pérez Jurado, Luis Alberto
Turro, Ernest
author Greene, Daniel
author_facet Greene, Daniel
Sevilla-Porras, Marta
Pérez Jurado, Luis Alberto
Turro, Ernest
author_role author
author2 Sevilla-Porras, Marta
Pérez Jurado, Luis Alberto
Turro, Ernest
author2_role author
author
author
dc.subject.none.fl_str_mv Neurodevelopmental disorders
Sequencing
topic Neurodevelopmental disorders
Sequencing
description The major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder. By genetic association, we identified recurrent de novo single-nucleotide mutations at nucleotide positions 4 and 35 of RNU2-2 in nine cases. We replicated this finding in 16 additional cases, bringing the total to 25. We estimate that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome. The disorder is characterized by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype. We found that U2-2 and canonical U2-1 were similarly expressed in blood. Despite mutant U2-2 being expressed in patient blood samples, we found no evidence of missplicing. Our findings cement the role of major spliceosomal snRNAs in the etiologies of neurodevelopmental disorders.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/10230/73390
http://dx.doi.org/10.1038/s41588-025-02159-5
https://hdl.handle.net/10230/73390
url https://hdl.handle.net/10230/73390
http://dx.doi.org/10.1038/s41588-025-02159-5
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature Genetics. 2025;57(6):1367-73
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
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