Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/98747
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Type: Journal article
Title: THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability
Author: Kumar, R.
Corbett, M.
Van Bon, B.
Woenig, J.
Weir, L.
Douglas, E.
Friend, K.
Gardner, A.
Shaw, M.
Jolly, L.
Tan, C.
Hunter, M.
Hackett, A.
Field, M.
Palmer, E.
Leffler, M.
Rogers, C.
Boyle, J.
Bienek, M.
Jensen, C.
et al.
Citation: American Journal of Human Genetics, 2015; 97(2):302-310
Publisher: Elsevier
Issue Date: 2015
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Raman Kumar, Mark A. Corbett, Bregje W.M. van Bon, Joshua A. Woenig, Lloyd Weir, Evelyn Douglas, Kathryn L. Friend, Alison Gardner, Marie Shaw, Lachlan A. Jolly, Chuan Tan, Matthew F. Hunter, Anna Hackett, Michael Field, Elizabeth E. Palmer, Melanie Leffler, Carolyn Rogers, Jackie Boyle, Melanie Bienek, Corinna Jensen, Griet Van Buggenhout, Hilde Van Esch, Katrin Hoffmann, Martine Raynaud, Huiying Zhao, Robin Reed, Hao Hu, Stefan A. Haas, and Eric Haan
Abstract: Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
Keywords: Chromosomes, Human, X
Rights: ©2015 by The American Society of Human Genetics. All rights reserved.
RMID: 0030031697
DOI: 10.1016/j.ajhg.2015.05.021
Grant ID: http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/nhmrc/1041920
Appears in Collections:Paediatrics publications

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