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

Authors :
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
Guibaud, Laurent
Source :
Proceedings of the National Academy of Sciences of the United States of America; 2/28/2023, Vol. 120 Issue 9, p1-11, 46p
Publication Year :
2023

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]

Details

Language :
English
ISSN :
00278424
Volume :
120
Issue :
9
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
162148674
Full Text :
https://doi.org/10.1073/pnas.2102569120