Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/124012
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Type: Journal article
Title: Expanding clinical presentations due to variations in THOC2 mRNA nuclear export factor
Author: Kumar, R.
Palmer, E.
Gardner, A.E.
Carroll, R.
Banka, S.
Abdelhadi, O.
Donnai, D.
Elgersma, Y.
Curry, C.J.
Gardham, A.
Suri, M.
Malla, R.
Brady, L.I.
Tarnopolsky, M.
Azmanov, D.N.
Atkinson, V.
Black, M.
Baynam, G.
Dreyer, L.
Hayeems, R.Z.
et al.
Citation: Front Mol Neurosci, 2020; 13
Publisher: Frontiers
Issue Date: 2020
ISSN: 1662-5099
1662-5099
Statement of
Responsibility: 
Raman Kumar, Elizabeth Palmer, Alison E. Gardner, Renee Carroll, Siddharth Banka ... Jozef Gecz ... et al.
Abstract: Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in euro developmental 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.
Keywords: THOC2; intellectual disability; mRNA export; microdeletion; neurodevelopmental disorders
Rights: © 2020 Kumar, Palmer, Gardner, Carroll, Banka, Abdelhadi, Donnai, Elgersma, Curry, Gardham, Suri, Malla, Brady, Tarnopolsky, Azmanov, Atkinson, Black, Baynam, Dreyer, Hayeems, Marshall, Costain, Wessels, Baptista, Drummond, Leffler, Field and Gecz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
RMID: 1000016909
DOI: 10.3389/fnmol.2020.00012
Grant ID: http://purl.org/au-research/grants/nhmrc/1091593
http://purl.org/au-research/grants/nhmrc/1163240
http://purl.org/au-research/grants/arc/170103090
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Medicine publications

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