Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy.
Por:
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 T, 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 and Turro E
Publicada:
1 jun 2025
Ahead of Print:
10 abr 2025
Resumen:
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.
Filiaciones:
Greene D:
Department of Medicine, University of Cambridge, Cambridge, UK
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
De Wispelaere K:
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
Lees J:
Bristol Medical School, University of Bristol, Bristol, UK
Codina-Solà M:
Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Medicine Genetics Group Vall d'Hebron Research Institute, Barcelona, Spain
Jensson BO:
deCODE genetics/AMGEN Inc., Reykjavik, Iceland
Hales E:
NIHR BioResource, Cambridge University Hospitals, Cambridge, UK
Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Katrinecz A:
NIHR BioResource, Cambridge University Hospitals, Cambridge, UK
Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Nieto Molina E:
Andalusian Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain
Pascoal S:
NIHR BioResource, Cambridge University Hospitals, Cambridge, UK
Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Pfundt R:
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Schot R:
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Sevilla Porras M:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Sleutels F:
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Valenzuela I:
Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Medicine Genetics Group Vall d'Hebron Research Institute, Barcelona, Spain
Wijngaard R:
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Arroyo Carrera I:
Pediatric Department, Hospital San Pedro de Alcántara, Cáceres, Spain
Atton G:
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
Casas-Alba D:
Clinical Genetics Department and Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
Donnelly D:
Department of Medical Genetics, Belfast City Hospital, Belfast, UK
Duat Rodríguez A:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Genetics Department, Hospital Niño Jesús, Madrid, Spain
Fernández Garoz B:
Genetics Department, Hospital Niño Jesús, Madrid, Spain
Foulds N:
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
García-Navas Núñez D:
Pediatric Department, Hospital San Pedro de Alcántara, Cáceres, Spain
González Alguacil E:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Genetics Department, Hospital Niño Jesús, Madrid, Spain
Jarvis J:
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK
Kant SG:
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Madrigal Bajo I:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona and Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Martinez-Monseny T:
Clinical Genetics Department and Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
McKee S:
Department of Medical Genetics, Belfast City Hospital, Belfast, UK
Ortiz Cabrera NV:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Genetics Department, Hospital Niño Jesús, Madrid, Spain
Rodríguez-Revenga Bodi L:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Biochemistry and Molecular Genetics Department, Hospital Clinic of Barcelona and Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Sariego Jamardo A:
Neuropediatric Department, Pediatric Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain
Stefansson K:
deCODE genetics/AMGEN Inc., Reykjavik, Iceland
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
Sulem P:
deCODE genetics/AMGEN Inc., Reykjavik, Iceland
Suri M:
Clinical Genetics, Nottingham University Hospital NHS Trust, Nottingham, UK
Van Karnebeek C:
Departments of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam Gastro-Enterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands
Vasudevan P:
Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK
Vega Pajares AI:
Genetics Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain
Carracedo Á:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Genomic Medicine Group, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, Santiago de Compostela, Spain
Galician Foundation of Genomic Medicine, IDIS, Galician Service of Health, Santiago de Compostela, Spain
Engelen M:
Department of Pediatric Neurology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
Lapunzina P:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Institute for Medical and Molecular Genetics (INGEMM), IdiPAZ, Madrid, Spain
Morgan NP:
NIHR BioResource, Cambridge University Hospitals, Cambridge, UK
Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Morte B:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Rump P:
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Stirrups K:
NIHR BioResource, Cambridge University Hospitals, Cambridge, UK
Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Tizzano EF:
Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Medicine Genetics Group Vall d'Hebron Research Institute, Barcelona, Spain
Barakat TS:
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
O'Donoghue M:
Neurology, Nottingham University Hospital NHS Trust, Nottingham, UK
Pérez-Jurado LA:
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Genetics Service, Hospital del Mar and Hospital del Mar Research Institute, Barcelona, Spain
Freson K:
Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
Mumford AD:
Bristol Medical School, University of Bristol, Bristol, UK
NHS South West Genomic Medicine Service Alliance, Bristol, UK
Turro E:
Department of Medicine, University of Cambridge, Cambridge, UK
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Green Submitted, hybrid
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