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Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor.
- Source :
- Frontiers in Molecular Neuroscience; 2/11/2020, Vol. 13, p1-15, 15p
- Publication Year :
- 2020
-
Abstract
- Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals' has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted. [ABSTRACT FROM AUTHOR]
- Subjects :
- MESSENGER RNA
PROTEIN stability
GROWTH disorders
EXPORTS
LANGUAGE disorders
Subjects
Details
- Language :
- English
- ISSN :
- 16625099
- Volume :
- 13
- Database :
- Complementary Index
- Journal :
- Frontiers in Molecular Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 141685152
- Full Text :
- https://doi.org/10.3389/fnmol.2020.00012