Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish

Article Article scientifique Article Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish eng 2023-02-21 2023-02-21 author Khatri Deepak 0000-0003-4552-5786 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Putoux Audrey Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Cologne Audric Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Kaltenbach Sophie Department of Histology Embryology and Cytogenetics, Assistance Publique - Hôpitaux de Paris, Necker-Enfants Malades Hospital, University of Paris, 75015 Paris, France author Besson Alicia Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Bertiaux Eloise Department of Cell Biology, Sciences III, University of Geneva, 1211-Geneva, Switzerland 917034 author Guguin Justine 0000-0001-9616-4867 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Fendler Adèle 0000-0003-0197-3747 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Dupont Marie A. Laboratory of hereditary kidney diseases, Imagine Institute, U1163 INSERM, University of Paris, 75015 Paris, France author Benoit-Pilven Clara Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Qebibo Leila 0000-0003-4850-0162 Département de Génétique, Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Assistance Publique - Hôpitaux de Paris, Sorbonne University, Trousseau Hospital, 75012 Paris, France author Ahmed-Elie Samira Département de Génétique, Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Assistance Publique - Hôpitaux de Paris, Sorbonne University, Trousseau Hospital, 75012 Paris, France author Audebert-Bellanger Séverine Department of Genetics, Clinical Genetics Unit, Centre de Compétence Anomalies du Développement et Syndromes Polymalformatifs, Centre Hospitalier Universitaire Morvan, 29200 Brest, France author Blanc Pierre Laboratoire SeqOIA–PFMG2025, 75014 Paris, France 813671 author Rambaud Thomas Laboratoire SeqOIA–PFMG2025, 75014 Paris, France author Castelle Martin Hematology-Immunology Unit, Assistance Publique - Hôpitaux de Paris, Necker-Enfants Malades Hospital, 75015 Paris, France author Cornen Gaëlle Pediatric service, Centre Hospitalier Morlaix, 29600 Morlaix, France author Grotto Sarah Clinical Genetics Unit, Maternité Port-Royal, Assistance Publique - Hôpitaux de Paris, Cochin Broca Hôtel-Dieu Hospitals 75014 Paris, France author Guët Agnès Neonatal and Pediatric Units, Louis-Mourier Hospital, 92700 Colombes, France author Guibaud Laurent Pediatric and Fetal Imaging, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, 69500 Bron, France author Michot Caroline Clinical Genetics Department, Centre de Référence Maladies Rares–Maladies Osseuses Constitutionnelles, Assistance Publique - Hôpitaux de Paris, Necker-Enfants Malades Hospital, 75015 Paris, France author Odent Sylvie Service de Génétique Clinique, Centre Hospitalier Universitaire Rennes, Centre de référence Anomalies du développement et syndromes malformatifs, Univ Rennes, CNRS, INSERM, Institut de Génétique et Développement de Rennes UMR 6290/ Equipe de Recherche Labellisée 1305, 35000 Rennes, France author Ruaud Lyse 0000-0003-4940-5896 NeuroDiderot, UMR1141, University of Paris, 75019 Paris, France author Sacaze Elise 0000-0001-9138-4852 Pediatric Service, Centre Hospitalier Régional Universitaire Brest, 29200 Brest, France author Hamel Virginie 0000-0001-5092-2343 Department of Cell Biology, Sciences III, University of Geneva, 1211-Geneva, Switzerland 846734 Département de biologie moléculaire et cellulaire (MOCEL) author Bordonné Rémy 0000-0002-1445-5802 Institute of Molecular Genetics of Montpellier, UMR5535 CNRS, University of Montpellier, 34000 Montpellier, France author Leutenegger Anne-Louise NeuroDiderot, UMR1141, University of Paris, 75019 Paris, France author Edery Patrick 0000-0001-8976-5832 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Burglen Lydie 0000-0002-1119-6809 Département de Génétique, Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Assistance Publique - Hôpitaux de Paris, Sorbonne University, Trousseau Hospital, 75012 Paris, France author Attié-Bitach Tania Department of Histology Embryology and Cytogenetics, Assistance Publique - Hôpitaux de Paris, Necker-Enfants Malades Hospital, University of Paris, 75015 Paris, France author Mazoyer Sylvie 0000-0002-2135-0160 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France author Delous Marion 0000-0003-2666-4457 Université Claude Bernard Lyon 1, INSERM, CNRS, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292,Genetics of Neurodevelopment Team, 69500 Bron, France 1-11 e2102569120 10.1073/pnas.2102569120 36802443 0027-8424 PMC9992838 https://pnas.org/doi/10.1073/pnas.2102569120 <p> In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC , has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC -associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing. </p> U4atac Genetic disease Minor introns Primary cilium Splicing Dewey 570 European Molecular Biology Organization ALTF-284-2019 Novartis StiftungÂ fÃ¼rÂ Medizinisch-Biologische Forschung (Novartis Foundation for Medical-Biological Research) 18B112 Fondation Maladies Rares 20161207 Agence Nationale de la Recherche (ANR) ANR-18CE12-0007-01 46 Département de biologie cellulaire 165 false Proceedings of the National Academy of Sciences of the United States of America 120 9 8b83729e-1ae7-4e4e-a3f2-4e82ec37ed9f Article (Published version) Public HAMEL02.pdf 3465783 application/pdf CC BY-NC-ND-4.0 1954003da9c967668c99f93bb00545dc2f948350ad0c9dbd46ceb541962c0213 openAccess Faculté des sciences / Section de biologie / Département de biologie cellulaire

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Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish	Proceedings of the National Academy of Sciences of the United States of America			2023	105	60

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Blanc, Pierre