Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment

Rudrarup Bhattacharjee, Lachlan A. Jolly, Mark A. Corbett, Ing Chee Wee, Sushma R. Rao, Alison E. Gardner, Tarin Ritchie, Eline J. H. Hugte, Ummi Ciptasari, Sandra Piltz, Jacqueline E. Noll, Nazzmer Nazri, Clare L. Eyk, Melissa White, Dani Fornarino, Cathryn Poulton, Gareth Baynam, Lyndsey E. Collins-Praino, Marten F. Snel, Nael Nadif Kasri, Kim M. Hemsley, Paul Q. Thomas, Raman Kumar and Jozef Gecz ()
Additional contact information
Rudrarup Bhattacharjee: The University of Adelaide
Lachlan A. Jolly: The University of Adelaide
Mark A. Corbett: The University of Adelaide
Ing Chee Wee: The University of Adelaide
Sushma R. Rao: The University of Adelaide
Alison E. Gardner: The University of Adelaide
Tarin Ritchie: The University of Adelaide
Eline J. H. Hugte: Cognition, and Behavior
Ummi Ciptasari: Cognition, and Behavior
Sandra Piltz: The University of Adelaide
Jacqueline E. Noll: University of Adelaide and Precision Cancer Medicine Theme, Solid Tumour Program, South Australian Health and Medical Research Institute
Nazzmer Nazri: The University of Adelaide
Clare L. Eyk: The University of Adelaide
Melissa White: The University of Adelaide
Dani Fornarino: The University of Adelaide
Cathryn Poulton: King Edward Memorial Hospital
Gareth Baynam: King Edward Memorial Hospital
Lyndsey E. Collins-Praino: The University of Adelaide
Marten F. Snel: The University of Adelaide
Nael Nadif Kasri: Cognition, and Behavior
Kim M. Hemsley: The University of Adelaide
Paul Q. Thomas: The University of Adelaide
Raman Kumar: The University of Adelaide
Jozef Gecz: The University of Adelaide

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45121-5

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