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

ABSTRACT: 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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Sushma Rao

LAB HEAD: Raman Sharma

PROVIDER: PXD040358 | Pride | 2024-02-12

REPOSITORIES: Pride

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Compromised THOC2, a TREX mRNA export complex scaffold protein, leads to R-loop accumulation, DNA damage and adverse neurodevelopmental outcomes in mice and men

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