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...
| Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | article |
| Status: | Published version |
| Publication Date: | 2025 |
| Country: | España |
| Institution: | Fundació Sant Joan de Déu |
| Repository: | r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
| OAI Identifier: | oai:fsjd.fundanetsuite.com:p28491 |
| Online Access: | https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28491 |
| Access Level: | Open access |
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Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy.Greene DDe Wispelaere KLees JCodina-Solà MJensson BOHales EKatrinecz ANieto Molina EPascoal SPfundt RSchot RSevilla Porras MSleutels FValenzuela IWijngaard RArroyo Carrera IAtton GCasas-Alba DDonnelly DDuat Rodríguez AFernández Garoz BFoulds NGarcía-Navas Núñez DGonzález Alguacil EJarvis JKant SGMadrigal Bajo IMartinez-Monseny AFMcKee SOrtiz Cabrera NVRodríguez-Revenga Bodi LSariego Jamardo AStefansson KSulem PSuri MVan Karnebeek CVasudevan PVega Pajares AICarracedo ÁEngelen MLapunzina PMorgan NPMorte BRump PStirrups KTizzano EFBarakat TSO'Donoghue MPérez-Jurado LAFreson KMumford ADTurro EThe 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 PORTFOLIO2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28491NATURE GENETICSISSN: 10614036ISSNe: 15461718reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p284912026-05-27T12:37:41Z |
| 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 D |
| 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 D De Wispelaere K Lees J Codina-Solà M Jensson BO Hales E Katrinecz A Nieto Molina E Pascoal S Pfundt R Schot R Sevilla Porras M Sleutels F Valenzuela I Wijngaard R Arroyo Carrera I Atton G Casas-Alba D Donnelly D Duat Rodríguez A Fernández Garoz B Foulds N García-Navas Núñez D González Alguacil E Jarvis J Kant SG Madrigal Bajo I Martinez-Monseny AF McKee S Ortiz Cabrera NV Rodríguez-Revenga Bodi L Sariego Jamardo A Stefansson K Sulem P Suri M Van Karnebeek C Vasudevan P Vega Pajares AI Carracedo Á Engelen M Lapunzina P Morgan NP Morte B Rump P Stirrups K Tizzano EF Barakat TS O'Donoghue M Pérez-Jurado LA Freson K Mumford AD Turro E |
| author |
Greene D |
| author_facet |
Greene D De Wispelaere K Lees J Codina-Solà M Jensson BO Hales E Katrinecz A Nieto Molina E Pascoal S Pfundt R Schot R Sevilla Porras M Sleutels F Valenzuela I Wijngaard R Arroyo Carrera I Atton G Casas-Alba D Donnelly D Duat Rodríguez A Fernández Garoz B Foulds N García-Navas Núñez D González Alguacil E Jarvis J Kant SG Madrigal Bajo I Martinez-Monseny AF McKee S Ortiz Cabrera NV Rodríguez-Revenga Bodi L Sariego Jamardo A Stefansson K Sulem P Suri M Van Karnebeek C Vasudevan P Vega Pajares AI Carracedo Á Engelen M Lapunzina P Morgan NP Morte B Rump P Stirrups K Tizzano EF Barakat TS O'Donoghue M Pérez-Jurado LA Freson K Mumford AD Turro E |
| author_role |
author |
| author2 |
De Wispelaere K Lees J Codina-Solà M Jensson BO Hales E Katrinecz A Nieto Molina E Pascoal S Pfundt R Schot R Sevilla Porras M Sleutels F Valenzuela I Wijngaard R Arroyo Carrera I Atton G Casas-Alba D Donnelly D Duat Rodríguez A Fernández Garoz B Foulds N García-Navas Núñez D González Alguacil E Jarvis J Kant SG Madrigal Bajo I Martinez-Monseny AF McKee S Ortiz Cabrera NV Rodríguez-Revenga Bodi L Sariego Jamardo A Stefansson K Sulem P Suri M Van Karnebeek C Vasudevan P Vega Pajares AI Carracedo Á Engelen M Lapunzina P Morgan NP Morte B Rump P Stirrups K Tizzano EF Barakat TS O'Donoghue M Pérez-Jurado LA Freson K Mumford AD Turro E |
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author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| 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 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28491 |
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https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28491 |
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Inglés |
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Inglés |
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info:eu-repo/semantics/openAccess |
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openAccess |
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NATURE PORTFOLIO |
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NATURE PORTFOLIO |
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NATURE GENETICS ISSN: 10614036 ISSNe: 15461718 reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname:Fundació Sant Joan de Déu |
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r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
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r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu |
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