Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
Date
2024
Authors
Bhattacharjee, R.
Jolly, L.A.
Corbett, M.A.
Wee, I.C.
Rao, S.R.
Gardner, A.E.
Ritchie, T.
van Hugte, E.J.H.
Ciptasari, U.
Piltz, S.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Nature Communications, 2024; 15(1):1210-1-1210-5
Statement of Responsibility
Rudrarup Bhattacharjee, Lachlan A. Jolly, Mark A. Corbett, Ing Chee Wee, Sushma R. Rao, Alison E. Gardner, Tarin Ritchie, Eline J. H. van Hugte, Ummi Ciptasari, Sandra Piltz, Jacqueline E. Noll, Nazzmer Nazri, ClareL. vanEyk, Melissa White, Dani Fornarino, Cathryn Poulton, Gareth Baynam, Lyndsey E.Collins-Praino, MartenF. Snel, Nael Nadif Kasri, Kim M.Hemsley, Paul Q. Thomas, Raman Kumar, Jozef Gecz
Conference Name
Abstract
We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37–38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37–38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.