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

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• The THOC2 gene, encoding a key subunit of the TREX complex, is implicated in neurodevelopmental disorders.
• Intellectual disability (ID) is a core phenotype associated with THOC2 gene variants.
• The molecular pathology underlying THOC2-related neurodevelopmental conditions remains largely uncharacterized.

Purpose of the Study:

• To investigate the molecular mechanisms of THOC2 gene dysfunction in a neurodevelopmental disorder.
• To generate and characterize a mouse model mimicking patient phenotypes associated with THOC2 variants.
• To elucidate the cellular and molecular consequences of compromised THOC2/TREX complex function.

Main Methods:

• Generation of a hypomorphic Thoc2 exon 37-38 deletion mouse model.
• Phenotypic characterization of Thoc2 mutant mice, including behavioral and neurological assessments.
• Analysis of brain development, R-loop accumulation, DNA damage, and cell death in Thoc2 mutant mice.

Main Results:

• Thoc2 mutant mice exhibit reduced size, weight, and deficits in learning, memory, and sensorimotor functions.
• Compromised THOC2/TREX function significantly impacts mouse brain development.
• R-loop accumulation, DNA damage, and cell death are observed in the brains of Thoc2 mutant mice.

Conclusions:

• Perturbed R-loop homeostasis and DNA damage are central to the pathophysiology of THOC2 syndrome.
• The study provides insights into the molecular basis of THOC2-related neurodevelopmental disorders.
• The mouse model serves as a valuable tool for further research into THOC2 syndrome and potential therapeutic strategies.