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. van Hugte, Ummi Ciptasari, Sandra Piltz, Jacqueline E. Noll, Nazzmer Nazri, Clare L. van Eyk, Melissa White, Dani Fornarino, Cathryn Poulton, Gareth Baynam, Lyndsey E. Collins-Praino, Marten F. Snel, Nael Nadif KasriKim M. Hemsley, Paul Q. Thomas, Raman Kumar, Jozef Gecz

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1210
Number of pages1
JournalNature Communications
Issue number1
Publication statusPublished or Issued - 8 Feb 2024

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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