Search

Your search keyword '"U4atac"' showing total 3 results
Start Over Descriptor "U4atac"
3 results on '"U4atac"'

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

Author

Khatri, Deepak, Putoux, Audrey, Cologne, Audric, Kaltenbach, Sophie, Besson, Alicia, Bertiaux, Eloïse, Guguin, Justine, Fendler, Adèle, Dupont, Marie A., Benoit-Pilven, Clara, Qebibo, Leila, Samira Ahmed-Elie, Audebert-Bellanger, Séverine, Blanc, Pierre, Rambaud, Thomas, Castelle, Martin, Cornen, Gaëlle, Grotto, Sarah,  Guët, Agnès, and Guibaud, Laurent

Subjects
*SMALL nuclear RNA, *GROWTH disorders, *SKELETAL dysplasia, *JOUBERT syndrome, *BRACHYDANIO, *MINORS, *FIREPROOFING agents
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

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

Author

Deepak Khatri, Audrey Putoux, Audric Cologne, Sophie Kaltenbach, Alicia Besson, Eloïse Bertiaux, Justine Guguin, Adèle Fendler, Marie A. Dupont, Clara Benoit-Pilven, Leila Qebibo, Samira Ahmed-Elie, Séverine Audebert-Bellanger, Pierre Blanc, Thomas Rambaud, Martin Castelle, Gaëlle Cornen, Sarah Grotto, Agnès Guët, Laurent Guibaud, Caroline Michot, Sylvie Odent, Lyse Ruaud, Elise Sacaze, Virginie Hamel, Rémy Bordonné, Anne-Louise Leutenegger, Patrick Edery, Lydie Burglen, Tania Attié-Bitach, Sylvie Mazoyer, Marion Delous, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Genève = University of Geneva (UNIGE), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital Morvan [Brest], CH Morlaix, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Louis Mourier - AP-HP [Colombes], Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Hôpital Robert Debré, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), This work was supported by CNRS, Inserm, Université de Montpellier, Université Paris 7 and Université Lyon 1 through recurrent funding, the Fondation Maladies Rares ('Small Animal Models and Rare Diseases' program, no. 20161207), the Agence Nationale de la Recherche (no. ANR-18CE12-0007-01), and the Fondation pour la recherche sur le Cerveau « Espoir en tête » (confocal microscope). E.B. was supported by an European Molecular Biology Organization long-term fellowship (ALTF-284-2019) and the Novartis Foundation for medical-biological Research (18B112)., and ANR-18-CE12-0007,U4ATAC-BRAIN,Rôle de l'épissage mineur dans le développement cérébral(2018)

Subjects
minor introns, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, MESH: Humans, MESH: Mutation, MESH: Fetal Growth Retardation, MESH: RNA, Small Nuclear, U4atac, splicing, genetic disease, MESH: Ciliopathies, MESH: Animals, MESH: Zebrafish, MESH: Female, MESH: Spliceosomes, primary cilium
Abstract

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.

Published
2023
Full Text
View/download PDF

3. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene.

Author

Nagy, R, Wang, H, Albrecht, B, Wieczorek, D, Gillessen- Kaesbach, G, Haan, E, Meinecke, P, de la Chapelle, A, and Westman, JA

Subjects
*DWARFISM, *MICROCEPHALY, *GENETIC mutation, *ALLELES, *STANDARD deviations, *TRANSCRIPTION factors, *PHYSIOLOGY
Abstract

Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, Meinecke P, de la Chapelle A, Westman JA. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results