PXD040358-1

PXD040358 is an original dataset announced via ProteomeXchange.

Title	Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment
Description	We implicated the X-chromosome THOC2 gene, which encodes largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically variable neurodevelopmental disorder with intellectual disability as the core phenotype. To study how compromised function of this essential eukaryotic gene leads to NDD outcomes, we generated a clinically-relevant 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 (Thoc2/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 Thoc2/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.
HostingRepository	PRIDE
AnnounceDate	2024-02-12
AnnouncementXML	Submission_2024-02-11_19:06:15.383.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sushma Rao
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	methylthiolated residue; monohydroxylated residue; deamidated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-23 03:56:35	ID requested
⏵ 1	2024-02-11 19:06:15	announced
2	2024-10-22 06:29:02	announced	2024-10-22: Updated project metadata.

10.1038/S41467-024-45121-5;

submitter keyword: Brain, Mice,Thoc2, Proteomics

Raman Sharma
contact affiliation	Adelaide Medical School Faculty of Health and Medical Sciences University of Adelaide
contact email	raman.sharma@adelaide.edu.au
lab head
Sushma Rao
contact affiliation	South Australian Health and Medical Research Institute University of Adelaide
contact email	sushma.rao@sahmri.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040358
     1. Label: PRIDE project
     2. Name: Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment