| Title: |
A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids |
| Authors: |
Guguin, Justine; Chen, Ting-Yu; Cuinat, Silvestre; Besson, Alicia; Bertiaux, Eloïse; Boutaud, Lucile; Ardito, Nolan; Imaz Murguiondo, Miren; Cabet, Sara; Hamel, Virginie; Thomas, Sophie; Pain, Bertrand; Edery, Patrick; Putoux, Audrey; Tang, Tang, K; Mazoyer, Sylvie; Delous, Marion |
| Contributors: |
Genetics of Neurodevelopment (CRNL-GENDEV); 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)-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); Institute of Biomedical Sciences Taipei (IBMS Sinica); Academia Sinica; 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); Paediatrics Service, Hospital Zumarraga, Gipuzkoa; Hôpital Femme Mère Enfant CHU - HCL (HFME); Hospices Civils de Lyon (HCL); Physiopathologie et génétique du neurone et du muscle (PGNM); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Université de Lyon |
| Source: |
ISSN: 1553-7390. |
| Publisher Information: |
CCSD; Public Library of Science |
| Publication Year: |
2024 |
| Collection: |
Université Jean Monnet – Saint-Etienne: HAL |
| Subject Terms: |
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39680576; PUBMED: 39680576; PUBMEDCENTRAL: PMC11684760; WOS: 001379153000004 |
| DOI: |
10.1371/journal.pgen.1011517 |
| Availability: |
https://hal.science/hal-04884707; https://hal.science/hal-04884707v1/document; https://hal.science/hal-04884707v1/file/24_2024c_Guguin%20et%20al,%20PLoS%20Genet%20-%20RTTN.pdf; https://doi.org/10.1371/journal.pgen.1011517 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.A9917826 |
| Database: |
BASE |