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Autor
Afenjar, Alexandra 1 Agolini, Emanuele 1 Akizu, Naiara 1 Amiel, Jeanne 1 Aneja, Anushree 1 Arena, Alessia 1 Aznar-Laín, Gemma 1 Balci, Tugce B 1 Barnett, Christopher 1 Battig, Mark R 1 Bayat, Allan 1 Bendova, Sarka 1 Bhoj, Elizabeth J 1 Biswas, Sunita 1 Bosch, Daniëlle Gm 1 Boycott, Kym M 1 Brady, Lauren 1 Brooks, Alice S 1 Bruel, Ange-Line 1 Busa, Tiffany 1
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Pracoviště
APHP SU Reference Center for Intellec... 1 Adelaide Medical School and Robinson ... 1 Aix Marseille University Inserm U1251... 1 Ambry Genetics Aliso Viejo California... 1 Center for Applied Genomics and 1 Center for Development Behavior and G... 1 Central Michigan University College o... 1 Centro de Investigación Biomédica en ... 1 Children's Hospital of Eastern Ontari... 1 Cluster of Excellence Multiscale Bioi... 1 DZHK partner site Göttingen Göttingen... 1 Department for Epilepsy Genetics and ... 1 Department of Biology and Medical Gen... 1 Department of Biomedical and Health I... 1 Department of Clinical Genetics Cook ... 1 Department of Clinical Genetics Erasm... 1 Department of Clinical Genetics Sheff... 1 Department of Clinical Medicine Unive... 1 Department of Drug Design and Pharmac... 1 Department of Epilepsy Genetics and P... 1
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Autor
Afenjar, Alexandra 1 Agolini, Emanuele 1 Akizu, Naiara 1 Amiel, Jeanne 1 Aneja, Anushree 1 Arena, Alessia 1 Aznar-Laín, Gemma 1 Balci, Tugce B 1 Barnett, Christopher 1 Battig, Mark R 1 Bayat, Allan 1 Bendova, Sarka 1 Bhoj, Elizabeth J 1 Biswas, Sunita 1 Bosch, Daniëlle Gm 1 Boycott, Kym M 1 Brady, Lauren 1 Brooks, Alice S 1 Bruel, Ange-Line 1 Busa, Tiffany 1
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Pracoviště
APHP SU Reference Center for Intellec... 1 Adelaide Medical School and Robinson ... 1 Aix Marseille University Inserm U1251... 1 Ambry Genetics Aliso Viejo California... 1 Center for Applied Genomics and 1 Center for Development Behavior and G... 1 Central Michigan University College o... 1 Centro de Investigación Biomédica en ... 1 Children's Hospital of Eastern Ontari... 1 Cluster of Excellence Multiscale Bioi... 1 DZHK partner site Göttingen Göttingen... 1 Department for Epilepsy Genetics and ... 1 Department of Biology and Medical Gen... 1 Department of Biomedical and Health I... 1 Department of Clinical Genetics Cook ... 1 Department of Clinical Genetics Erasm... 1 Department of Clinical Genetics Sheff... 1 Department of Clinical Medicine Unive... 1 Department of Drug Design and Pharmac... 1 Department of Epilepsy Genetics and P... 1
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ProQuest Central od 2002-07-01
Open Access Digital Library od 1924-10-01
Open Access Digital Library od 1925-08-01
Nursing & Allied Health Database (ProQuest) od 2002-07-01
Health & Medicine (ProQuest) od 2002-07-01
PubMed
37962958
DOI
10.1172/jci171235
Knihovny.cz E-zdroje
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
- MeSH
- enzymy opravy DNA genetika MeSH
- genové regulační sítě MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- missense mutace MeSH
- neurovývojové poruchy * genetika MeSH
- sestřih RNA MeSH
- sestřihové faktory genetika MeSH
- spliceozomy * genetika MeSH
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- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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