Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Multiple TREX mRNA export complex subunits, including THOC2, are associated with neurodevelopmental disorders (NDDs), neurodegeneration, and cancer.
• Previous research implicated THOC2 variants in NDDs and other clinical conditions.

Purpose of the Study:

• To report new rare missense and deletion variants in the THOC2 gene.
• To investigate the impact of these variants on THOC2 protein stability and the TREX complex.
• To refine the clinical phenotype associated with THOC2-related NDDs.

Main Methods:

• Identification and characterization of 10 individuals with rare missense THOC2 variants and one with a microdeletion.
• Ex vivo variant testing and analysis of patient-derived cell lines.
• Assessment of TREX complex stability in response to THOC2 variants.

Main Results:

• Nine of 14 missense THOC2 variants led to reduced protein stability.
• Splicing-defective and deletion variants caused loss of THOC2 RNA binding domain regions.
• Reduced THOC2 stability destabilized the broader TREX complex, affecting other NDD-associated THOC subunits.

Conclusions:

• THOC2 variants contribute to NDDs through impaired protein and TREX complex stability.
• The core phenotype includes language disorder, intellectual disability (ID), and growth abnormalities.
• A subset of patients exhibits severe phenotypes including profound ID, hypotonia, and respiratory issues, warranting further investigation.