Scientific article
Open access

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

Publication date2023-02-21
First online date2023-02-21

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.

  • U4atac
  • Genetic disease
  • Minor introns
  • Primary cilium
  • Splicing
  • European Molecular Biology Organization - [ALTF-284-2019]
  • Novartis Stiftung für Medizinisch-Biologische Forschung (Novartis Foundation for Medical-Biological Research) - [18B112]
  • Fondation Maladies Rares - [20161207]
  • Agence Nationale de la Recherche (ANR) - [ANR-18CE12-0007-01]
Citation (ISO format)
KHATRI, Deepak et al. Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish. In: Proceedings of the National Academy of Sciences of the United States of America, 2023, vol. 120, n° 9, p. 1–11. doi: 10.1073/pnas.2102569120
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Article (Published version)
ISSN of the journal0027-8424

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