A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids
Taybi-Linder syndrome (TALS) is a rare autosomal recessive disorder characterized by severe microcephaly with abnormal gyral pattern, severe growth retardation and bone abnormalities. It is caused by pathogenic variants in the RNU4ATAC gene. Its transcript, the small nuclear RNA U4atac, is involved in the excision of ~850 minor introns. Here, we report a patient presenting with TALS features but no pathogenic variants were found in RNU4ATAC, instead the homozygous RTTN c.2953A>G variant was detected by whole-exome sequencing. After deciphering the impact of the variant on the RTTN protein function at centrosome in engineered RTTN-depleted RPE1 cells and patient fibroblasts, we analysed neural stem cells (NSC) derived from CRISPR/Cas9-edited induced pluripotent stem cells and revealed major cell cycle and mitotic abnormalities, leading to aneuploidy, cell cycle arrest and cell death. In cortical organoids, we discovered an additional function of RTTN in the self-organisation of NSC into neural rosettes, by observing delayed apico-basal polarization of NSC. Altogether, these defects contributed to a marked delay of rosette formation in RTTN-mutated organoids, thus impeding their overall growth and shedding light on mechanisms leading to microcephaly.
Authors
- Marion Delous (ORCID: https://orcid.org/0000-0003-2666-4457)
- Sylvie Mazoyer (ORCID: https://orcid.org/0000-0002-2135-0160)
- Alicia Besson (ORCID: https://orcid.org/0000-0002-2812-5927)
- Audrey Putoux (ORCID: https://orcid.org/0000-0001-5496-4604)
- Virginie Hamel (ORCID: https://orcid.org/0000-0001-5092-2343)
- T.-H. Chen (ORCID: https://orcid.org/0000-0001-7767-7106)
- Silvestre Cuinat (ORCID: https://orcid.org/0000-0002-0763-5661)
- Bertrand Pain (ORCID: https://orcid.org/0000-0002-1210-8444)
- Sara Cabet (ORCID: https://orcid.org/0000-0003-0115-2586)
- Sophie Thomas (ORCID: https://orcid.org/0000-0002-8569-3277)
- Eloïse Bertiaux (ORCID: https://orcid.org/0000-0001-6593-083X)
- Justine Guguin (ORCID: https://orcid.org/0000-0001-9616-4867)
- Tang K. Tang (ORCID: https://orcid.org/0000-0002-3660-0695)
- Lucile Boutaud (ORCID: https://orcid.org/0000-0003-0767-2822)
- Patrick Edery (ORCID: https://orcid.org/0000-0001-8976-5832)
- Miren Imaz Murguiondo
- Nolan Ardito
Institutions
- Université Claude Bernard Lyon 1 (FR)
- University of Geneva (CH)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Hôpital Femme Mère Enfant (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre de Recherche en Neurosciences de Lyon (FR)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Hospices Civils de Lyon (FR)
- Institut NeuroMyoGène (FR)
- Institut Cellule Souche et Cerveau (FR)
Publication Details
- Journal
- PLoS Genetics
- Published
- 2024-12-16
- DOI
- https://doi.org/10.1371/journal.pgen.1011517
- Citations
- 3
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- Fondation Jérôme Lejeune
- Ministry of Advanced Education and Skills Development
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Academia Sinica
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- National Science and Technology Council