Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy.
Year: 2024
Type: article
Abstract: 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.
Source: Apollo (University of Cambridge)
Authors: Greene, Daniel, De Wispelaere, Koenraad, Lees, Jon, Codina-Solà, Marta, Jensson, Brynjar O, Hales, Emma, Katrinecz, Andrea, Nieto Molina, Esther, Pascoal, Sonia, Pfundt, Rolph, Schot, Rachel, Sevilla Porras, Marta, Sleutels, Frank, Valenzuela, Irene, Wijngaard, Robin, Arroyo Carrera, Ignacio, Atton, Giles, Casas-Alba, Didac, Donnelly, Deirdre, Duat Rodríguez, Anna, Fernández Garoz, Bárbara, Foulds, Nicola, García-Navas Núñez, Deyanira, González Alguacil, Elena, Jarvis, Joanna, Kant, Sarina G, Madrigal Bajo, Irene, Martinez-Monseny, Antonio F, McKee, Shane, Ortiz Cabrera, Nelmar Valentina, Rodríguez-Revenga Bodi, Laia, Sariego Jamardo, Andrea, Stefansson, Kari, Sulem, Patrick, Suri, Mohnish, Van Karnebeek, Clara, Vasudevan, Pradeep, Vega Pajares, Ana Isabel, Carracedo, Ángel, Engelen, Marc, Lapunzina, Pablo, Morgan, Natasha P, Morte, Beatriz, Rump, Patrick, Stirrups, Kathy, Tizzano, Eduardo F, Barakat, Tahsin Stefan, O'Donoghue, Michael, Pérez-Jurado, Luis Alberto, Freson, Kathleen, Mumford, Andrew D, Turro, Ernest
Institutions: University of Cambridge, Icahn School of Medicine at Mount Sinai, KU Leuven, University of Bristol, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, deCODE Genetics (Iceland), Cambridge University Hospitals NHS Foundation Trust, NIHR BioResource, Radboud University Nijmegen, Radboud University Medical Center, Erasmus MC, Donders Institute for Brain, Cognition and Behaviour, University Hospital Southampton NHS Foundation Trust, Belfast City Hospital, Birmingham Women's Hospital, Institut de Recerca Sant Joan de Déu, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Citizens United for Research in Epilepsy, NHS Blood and Transplant, Wellcome Trust, Stichting Metakids, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, ZonMw, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Ministerio de Ciencia e Innovación, Vlaamse regering, National Institutes of Health, NIHR BioResource, Medical Research Council, Instituto de Salud Carlos III, Bijzonder Onderzoeksfonds UGent, European Regional Development Fund, National Heart, Lung, and Blood Institute
OpenAlex ID: W7110700089
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