Journal
FRONTIERS IN MOLECULAR NEUROSCIENCE
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2020.00012
Keywords
mRNA export; THOC2; intellectual disability; neurodevelopmental disorders; microdeletion
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Funding
- National Health and Medical Research Council (NHMRC) [APP1091593]
- NHMRC [APP1163240]
- Australian Research Council [170103090]
- Norm Saunders Complex Care Initiative
- SickKids Centre for Genetic Medicine
- University of Toronto McLaughlin Centre
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- [APP1041920]
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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.
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