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

Author

Listed:
  • Rudrarup Bhattacharjee

    (The University of Adelaide
    The University of Adelaide)

  • Lachlan A. Jolly

    (The University of Adelaide
    The University of Adelaide)

  • Mark A. Corbett

    (The University of Adelaide
    The University of Adelaide)

  • Ing Chee Wee

    (The University of Adelaide)

  • Sushma R. Rao

    (The University of Adelaide
    The University of Adelaide)

  • Alison E. Gardner

    (The University of Adelaide
    The University of Adelaide)

  • Tarin Ritchie

    (The University of Adelaide
    The University of Adelaide)

  • Eline J. H. Hugte

    (Cognition, and Behavior)

  • Ummi Ciptasari

    (Cognition, and Behavior)

  • Sandra Piltz

    (The University of Adelaide
    The University of Adelaide
    South Australian Health and Medical Research Institute)

  • 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
    Flinders University, Bedford Park)

  • Clare L. Eyk

    (The University of Adelaide
    The University of Adelaide)

  • Melissa White

    (The University of Adelaide
    The University of Adelaide
    South Australian Health and Medical Research Institute)

  • Dani Fornarino

    (The University of Adelaide
    The University of Adelaide)

  • Cathryn Poulton

    (King Edward Memorial Hospital)

  • Gareth Baynam

    (King Edward Memorial Hospital
    King Edward Memorial Hospital
    Perth Children’s Hospital)

  • Lyndsey E. Collins-Praino

    (The University of Adelaide)

  • Marten F. Snel

    (The University of Adelaide
    The University of Adelaide)

  • Nael Nadif Kasri

    (Cognition, and Behavior)

  • Kim M. Hemsley

    (The University of Adelaide
    Flinders University, Bedford Park)

  • Paul Q. Thomas

    (The University of Adelaide
    The University of Adelaide
    South Australian Health and Medical Research Institute)

  • Raman Kumar

    (The University of Adelaide
    The University of Adelaide)

  • Jozef Gecz

    (The University of Adelaide
    The University of Adelaide)

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.

Suggested Citation

  • 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 , 2024. "Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45121-5
    DOI: 10.1038/s41467-024-45121-5
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    References listed on IDEAS

    as
    1. Anusha P. Dias & Kobina Dufu & Haixin Lei & Robin Reed, 2010. "A role for TREX components in the release of spliced mRNA from nuclear speckle domains," Nature Communications, Nature, vol. 1(1), pages 1-10, December.
    2. Margarida Cardoso-Moreira & Jean Halbert & Delphine Valloton & Britta Velten & Chunyan Chen & Yi Shao & Angélica Liechti & Kelly Ascenção & Coralie Rummel & Svetlana Ovchinnikova & Pavel V. Mazin & Io, 2019. "Gene expression across mammalian organ development," Nature, Nature, vol. 571(7766), pages 505-509, July.
    3. Mary E. Dickinson & Ann M. Flenniken & Xiao Ji & Lydia Teboul & Michael D. Wong & Jacqueline K. White & Terrence F. Meehan & Wolfgang J. Weninger & Henrik Westerberg & Hibret Adissu & Candice N. Baker, 2016. "High-throughput discovery of novel developmental phenotypes," Nature, Nature, vol. 537(7621), pages 508-514, September.
    4. Thorsten Mosler & Francesca Conte & Gabriel M. C. Longo & Ivan Mikicic & Nastasja Kreim & Martin M. Möckel & Giuseppe Petrosino & Johanna Flach & Joan Barau & Brian Luke & Vassilis Roukos & Petra Beli, 2021. "R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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